Diaminediols for the treatment of Alzheimer&#39;s disease

ABSTRACT

The present invention relates to compounds of formula (I):  
                 
 
     useful in treating Alzheimer&#39;s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer&#39;s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. ProvisionalApplication Serial No. 60/304,305, filed Jul. 10, 2001, and U.S.Provisional Application Serial No. 60/334,480, filed Nov. 30, 2001.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention relates to diaminediols and to such compounds thatare useful in the treatment of Alzheimer's disease and related diseases.More specifically, it relates to such compounds that are capable ofinhibiting beta-secretase, an enzyme that cleaves amyloid precursorprotein to produce amyloid beta peptide (A beta), a major component ofthe amyloid plaques found in the brains of Alzheimer's sufferers.

[0004] 2. Background of the Invention

[0005] Alzheimer's disease (AD) is a progressive degenerative disease ofthe brain primarily associated with aging. Clinical presentation of ADis characterized by loss of memory, cognition, reasoning, judgment, andorientation. As the disease progresses, motor, sensory, and linguisticabilities are also affected until there is global impairment of multiplecognitive functions. These cognitive losses occur gradually, buttypically lead to severe impairment and eventual death in the range offour to twelve years.

[0006] Alzheimer's disease is characterized by two major pathologicobservations in the brain: neurofibrillary tangles and beta amyloid (orneuritic) plaques, comprised predominantly of an aggregate of a peptidefragment know as A beta. Individuals with AD exhibit characteristicbeta-amyloid deposits in the brain (beta amyloid plaques) and incerebral blood vessels (beta amyloid angiopathy) as well asneurofibrillary tangles. Neurofibrillary tangles occur not only inAlzheimer's disease but also in other dementia-inducing disorders. Onautopsy, large numbers of these lesions are generally found in areas ofthe human brain important for memory and cognition.

[0007] Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type (HCHWA-D), and other neurodegenerative disorders.Beta-amyloid is a defining feature of AD, now believed to be a causativeprecursor or factor in the development of disease. Deposition of A betain areas of the brain responsible for cognitive activities is a majorfactor in the development of AD. Beta-amyloid plaques are predominantlycomposed of amyloid beta peptide (A beta, also sometimes designatedbetaA4). A beta peptide is derived by proteolysis of the amyloidprecursor protein (APP) and is comprised of 39-42 amino acids. Severalproteases called secretases are involved in the processing of APP.

[0008] Cleavage of APP at the N-terminus of the A beta peptide bybeta-secretase and at the C-terminus by one or more gamma-secretasesconstitutes the beta-amyloidogenic pathway, i.e. the pathway by which Abeta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP,a secreted form of APP that does not result in beta-amyloid plaqueformation. This alternate pathway precludes the formation of A betapeptide. A description of the proteolytic processing fragments of APP isfound, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and5,942,400.

[0009] An aspartyl protease has been identified as the enzymeresponsible for processing of APP at the beta-secretase cleavage site.The beta-secretase enzyme has been disclosed using varied nomenclature,including BACE, Asp, and Memapsin. See, for example, Sinha et al., 1999,Nature 402:537-554 (p501) and published PCT application WO00/17369.

[0010] Several lines of evidence indicate that progressive cerebraldeposition of beta-amyloid peptide (A beta) plays a seminal role in thepathogenesis of AD and can precede cognitive symptoms by years ordecades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A betafrom neuronal cells grown in culture and the presence of A beta incerebrospinal fluid (CSF) of both normal individuals and AD patients hasbeen demonstrated. See, for example, Seubert et al., 1992, Nature359:325-327.

[0011] It has been proposed that A beta peptide accumulates as a resultof APP processing by beta-secretase, thus inhibition of this enzyme'sactivity is desirable for the treatment of AD. In vivo processing of APPat the beta-secretase cleavage site is thought to be a rate-limitingstep in A beta production, and is thus a therapeutic target for thetreatment of AD. See for example, Sabbagh, M., et al., 1997, Alz. Dis.Rev. 3, 1-19.

[0012] BACE1 knockout mice fail to produce A beta, and present a normalphenotype. When crossed with transgenic mice that over express APP, theprogeny show reduced amounts of A beta in brain extracts as comparedwith control animals (Luo et al., 2001 Nature Neuroscience 4:231-232).This evidence further supports the proposal that inhibition ofbeta-secretase activity and reduction of A beta in the brain provides atherapeutic method for the treatment of AD and other beta amyloiddisorders.

[0013] At present there are no effective treatments for halting,preventing, or reversing the progression of Alzheimer's disease.Therefore, there is an urgent need for pharmaceutical agents capable ofslowing the progression of Alzheimer's disease and/or preventing it inthe first place.

[0014] Compounds that are effective inhibitors of beta-secretase, thatinhibit beta-secretase-mediated cleavage of APP, that are effectiveinhibitors of A beta production, and/or are effective to reduce amyloidbeta deposits or plaques, are needed for the treatment and prevention ofdisease characterized by amyloid beta deposits or plaques, such as AD.

SUMMARY OF THE INVENTION

[0015] The invention encompasses the compounds of formula (I) shownbelow, pharmaceutical compositions containing the compounds and methodsemploying such compounds or compositions in the treatment of Alzheimer'sdisease and more specifically compounds that are capable of inhibitingbeta-secretase, an enzyme that cleaves amyloid precursor protein toproduce A-beta peptide, a major component of the amyloid plaques foundin the brains of Alzheimer's sufferers.

[0016] In one aspect, the invention provides compounds of the formula I:

[0017] and pharmaceutically acceptable salts thereof, wherein

[0018] R₁ is

[0019] C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, —S—(C₁-C₃)alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or

[0020] C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino, or

[0021] aryl, heteroaryl, heterocyclyl, aryl(C₁-C₆)alkyl-,heteroaryl(C₁-C₆)alkyl-, or heterocyclyl(C₁-C₆)alkyl-, where the ringportions of each are optionally substituted with 1, 2, 3, or 4 groupsindependently selected from halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅,—CO₂R, —N(R)COR′, —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino,—SO₂-monoalkylamino, —SO₂-dialkylamino, —C(═O)-amino,—C(═O)-monoalkylamino, —C(═O)-dialkylamino, —SO₂—(C₁-C₄) alkyl,

[0022] C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups whichare independently selected from halogen,

[0023] C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, —C₁-C₆ alkyl and mono- or dialkylamino,

[0024] C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, amino, mono- or dialkylamino and -C₁-C₃ alkyl, and

[0025] C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- ordialkylamino; and the heterocyclyl group is optionally furthersubstituted with oxo;

[0026] R and R′ independently are hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀alkylaryl or C₁-C₁₀ alkylheteroaryl;

[0027] R₁′ is phenyl-(C₁-C₆)alkyl- where the phenyl ring is optionallysubstituted with 1, 2, 3, or 4 groups independently selected fromhalogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′,—N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-monoalkylamino,—SO₂-dialkylamino, —C(═O)-amino, —C(═O)-monoalkylamino,—C(═O)-dialkylamino, —SO₂—(C₁-C₄) alkyl,

[0028] C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups whichare independently selected from halogen,

[0029] C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, —C₁-C₆ alkyl and mono- or dialkylamino,

[0030] C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, and

[0031] C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- ordialkylamino; and the heterocyclyl group is optionally furthersubstituted with oxo,

[0032]  with the proviso that R₁ and R₁′ are not simultaneouslyunsubstituted phenyl-(CH₂)—,

[0033] R₂₀ at each occurrence is independently H or C₁-C₆ alkyl;

[0034] R_(N) and R_(N)′, are independently R′₁₀₀, —SO₂R′₁₀₀,—(CRR′)₁₋₆R′₁₀₀, —C(═O)—(CRR′)₀₋₆R₁₀₀, —C(═O)—(CRR′)₁₋₆—O—R′₁₀₀,—C(═O)—(CRR′)₁₋₆—S—R′₁₀₀, or —C(═O)—(CRR′)₁₋₆—NR₁₀₀—R′₁₀₀;

[0035] R₁₀₀ and R′₁₀₀ independently represent aryl, heteroaryl,heterocyclyl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl,-heteroaryl-W-aryl, -heteroaryl-W-heteroaryl,-heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl,-heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl,—CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl, or—CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions ofeach are optionally substituted with 1, 2, or 3 groups independentlyselected from

[0036] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R′₁₀₂, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),—(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or

[0037] R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅groups, or

[0038] R₁₀₀ is —(C₁-C₆ alkyl)—O—(C₁-C₆ alkyl) or —(C₁-C₆ alkyl)—S—(C₁-C₆alkyl), each of which is optionally substituted with 1, 2, or 3 R₁₁₅groups, or

[0039] R₁₀₀ is C₃-C₈ cycloalkyl optionally substituted with 1, 2, or 3R₁₁₅ groups;

[0040] W is —(CH₂)₀₋₄—, —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, —CR(OH)— or —C(O)—;

[0041] R₁₀₂ and R₁₀₂′ independently are hydrogen, or

[0042] C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups thatare independently halogen, aryl or —R₁₁₀;

[0043] R₁₀₅ and R′₁₀₅ independently represent —H, —R₁₁₀, —R₁₂₀, C₃-C₇cycloalkyl, —(C₁-C₂ alkyl)—(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)—O —(C₁-C₃alkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ alkyl chain with onedouble bond and one triple bond, or

[0044] C₁-C₆ alkyl optionally substituted with —OH or —NH₂; or,

[0045] C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, or

[0046] R₁₀₅ and R′₁₀₅ together with the atom to which they are attachedform a 3 to 7 membered carbocylic ring, where one member is optionally aheteratom selected from —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, the ring beingoptionally substituted with 1, 2 or 3 independently selected R₁₄₀groups;

[0047] R₁₁₅ at each occurrence is independently halogen, —OH, —CO₂R₁₀₂,—C₁-C₆ thioalkoxy, —CO₂-phenyl, —NR₁₀₅R′₁₀₅, —SO₂—(C₁-C₈ alkyl),—C(═O)R₁₅₀, R₁₈₀, —CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅, —NH—CO—(C₁-C₆ alkyl),—NH—CO—R₁₁₀, —NH—CO—R₁₂₀, —NH—C(═O)—OH, —NH—C(═O)—OR,—NH—C(═O)—O—phenyl, —O—C(═O)—(C₁-C₆ alkyl), —O—C(═O)-amino,—O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl, —O—(C₁-C₆ alkyl)-CO₂H,—NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆ haloalkoxy;

[0048] R₁₃₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇cycloalkyl, —(CH₂)₀₋₂-(aryl), —(CH₂)₀₋₂-(heteroaryl), or—(CH₂)₀₋₂-(heterocyclyl);

[0049] R₁₄₀ is heterocyclyl optionally substituted with 1, 2, 3, or 4groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and ═O;

[0050] R₁₅₀ is hydrogen, C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇cycloalkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one doublebond and one triple bond, —R₁₁₀, —R₁₂₀, or

[0051] C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and halogen;

[0052] R₁₅₀′ is C₃-C₇ cycloalkyl, —(C₁-C₃ alkyl)-(C₃-C₇ cycloalkyl),C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and onetriple bond, —R₁₁₀, —R₁₂₀, or

[0053] C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and halogen;

[0054] R₁₈₀ is selected from morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl,each of which is optionally substituted with 1, 2, 3, or 4 groupsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and ═O;

[0055] R₁₁₀ is aryl optionally substituted with 1 or 2 R₁₂₅ groups;

[0056] R₁₂₅ at each occurrence is independently halogen, amino, mono- ordialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆alkyl)₂, —SO₂—(C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl, or —CO—N(C₁-C₆alkyl)₂, or

[0057] C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which isoptionally substituted with 1, 2, or 3 groups that are independentlyselected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, and mono- and dialkylamino, or

[0058] C₁-C₆ alkoxy optionally substituted with one, two or three ofhalogen;

[0059] R₁₂₀ is heteroaryl, which is optionally substituted with 1 or 2R₁₂₅ groups; and

[0060] R₁₃₀ is heterocyclyl optionally substituted with 1 or 2 R₁₂₅groups.

[0061] The invention also provides methods for the treatment orprevention of Alzheimer's disease, mild cognitive impairment Down'ssyndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type, cerebral amyloid angiopathy, other degenerative dementias,dementias of mixed vascular and degenerative origin, dementia associatedwith Parkinson's disease, dementia associated with progressivesupranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease compriseingadministration of a therapeutically effective amount of a compound orsalt of formula I, to a patient in need thereof.

[0062] Preferably, the patient is a human.

[0063] More preferably, the disease is Alzheimer's disease.

[0064] More preferably, the disease is dementia.

[0065] The invention also provides pharmaceutical compositionscomprising a compound or salt of formula I and at least onepharmaceutically acceptable carrier, solvent, adjuvant or diluent.

[0066] The invention also provides the use of a compound or saltaccording to formula I for the manufacture of a medicament.

[0067] The invention also provides the use of a compound or salt offormula I for the treatment or prevention of Alzheimer's disease, mildcognitive impairment Down's syndrome, Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, otherdegenerative dementias, dementias of mixed vascular and degenerativeorigin, dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, or diffuse Lewy body type of Alzheimer'sdisease.

[0068] The invention also provides compounds, pharmaceuticalcompositions, kits, and methods for inhibiting beta-secretase-mediatedcleavage of amyloid precursor protein (APP). More particularly, thecompounds, compositions, and methods of the invention are effective toinhibit the production of A-beta peptide and to treat or prevent anyhuman or veterinary disease or condition associated with a pathologicalform of A-beta peptide.

[0069] The compounds, compositions, and methods of the invention areuseful for treating humans who have Alzheimer's Disease (AD), forhelping prevent or delay the onset of AD, for treating patients withmild cognitive impairment (MCI), and preventing or delaying the onset ofAD in those patients who would otherwise be expected to progress fromMCI to AD, for treating Down's syndrome, for treating HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch Type, for treatingcerebral beta-amyloid angiopathy and preventing its potentialconsequences such as single and recurrent lobar hemorrhages, fortreating other degenerative dementias, including dementias of mixedvascular and degenerative origin, for treating dementia associated withParkinson's disease, dementia associated with progressive supranuclearpalsy, dementia associated with cortical basal degeneration, and diffuseLewy body type AD, and for treating frontotemporal dementias withparkinsonism (FTDP).

[0070] The compounds of the invention possess beta-secretase inhibitoryactivity. The inhibitory activities of the compounds of the invention isreadily demonstrated, for example, using one or more of the assaysdescribed herein or known in the art.

[0071] Unless the substituents for a particular formula are expresslydefined for that formula, they are understood to carry the definitionsset forth in connection with the preceeding formula to which theparticular formula makes reference.

[0072] The invention also provides methods of preparing the compounds ofthe invention and the intermediates used in those methods.

DETAILED DESCRIPTION OF THE INVENTION

[0073] As noted above, the invention provides compounds of formula I.

[0074] In the following description of preferred compounds, where asubstituent or group is not specifically defined, that substituent orgroup is as defined for formula I.

[0075] Preferred compounds of formula I include those of formula I-1,i.e., compounds of formula I wherein R₂₀ at each occurrence is H.

[0076] Preferred compounds of formula I and formula I-1 include those offormula I-2, i.e., compounds of the formula I or I-1 wherein

[0077] R₁ is

[0078] C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, —S—(C₁-C₃)alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or

[0079] C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino.

[0080] More preferred compounds of formula I-2 include those wherein

[0081] R₁ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, —S—(C₁-C₃)alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino.

[0082] Still more preferred compounds of formula I-2 include thosewherein

[0083] R₁ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from —SH, —C≡N, C₁-C₃ alkoxy, —S—(C₁-C₃)alkyl,amino, and mono- or dialkylamino.

[0084] Preferred compounds of the formula I-2 also include:

[0085] wherein R_(N), R₁′ and R_(N)′ are as defined for formula I.

[0086] Preferred compounds of formula I-1 and formula I-2 include thoseof formula I-3, i.e., compounds of formula I-1 or formula I-2 wherein

[0087] R₁′ is —CH₂-phenyl where the phenyl ring is optionallysubstituted with 1, 2, 3, or 4 groups independently selected fromhalogen, C₁-C₄ alkoxy, hydroxy, —NO₂, and

[0088] C₁-C₄ alkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from halogen, OH, SH, NH₂, NH(C₁-C₆ alkyl),N—(C₁-C₆ alkyl)(C₁-C₆ alkyl), C≡N, CF₃.

[0089] Still more preferred compounds of formula I-3 include thosewherein

[0090] R₁′ is —CH₂-phenyl where the phenyl ring is optionallysubstituted with 1 or 2 groups independently selected from halogen,C₁-C₂ alkyl, C₁-C₂ alkoxy, hydroxy, —CF₃, and —NO₂.

[0091] More preferred compounds of formula I-3 include those wherein

[0092] R₁′ is —CH₂-phenyl where the phenyl ring is unsubstituted or issubstituted with 2 groups independently selected from halogen, C₁-C₂alkyl, C₁-C₂ alkoxy, hydroxy, and —NO₂.

[0093] Still yet more preferred compounds of formula I-2 include thosewherein R₁′ is benzyl or 3,5-difluorobenzyl.

[0094] Other preferred compounds of formula I-1, I-2 and I-3 includecompounds of formula I-4, i.e., those of formula I-1, I-2, or I-3wherein

[0095] R_(N) is —C(═O)—(CRR′)₀₋₆R₁₀₀;

[0096] R₁₀₀ represents aryl, heteroaryl, heterocyclyl, -aryl-W-aryl,-aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl,-heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl,-heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl,-heterocyclyl-W-heterocyclyl, —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl, or—CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions ofeach are optionally substituted with 1, 2, or 3 groups independentlyselected from

[0097] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO_(R) ₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),—(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or

[0098] R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅groups.

[0099] Preferred compounds of formula I-4 include compounds wherein

[0100] R_(N) is —C(═O)—(CRR′)₀₋₆R₁₀₀; and

[0101] R₁₀₀ represents aryl, heteroaryl, heterocyclyl, where the ringportions of each are optionally substituted with 1, 2, or 3 groupsindependently selected from

[0102] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)_(0-4—SO) ₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),—(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or

[0103] R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅groups.

[0104] Still more preferred compounds of formula I-4 include compoundswherein

[0105] R_(N) is —C(═O)—R₁₀₀; and

[0106] R₁₀₀ represents aryl or heteroaryl where the ring portions ofeach are optionally substituted with 1, 2, or 3 groups independentlyselected from

[0107] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′,—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,—(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀) —(CH₂)₀₋₄—O—R₁₅₀′—COOH,—(CH₂)₀₋₄—S—(R₁₅₀), and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, or

[0108] R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅groups.

[0109] More preferred compounds of formula I-4 include compounds wherein

[0110] R_(N) is —C(═O)-aryl or —C(═O)-heteroaryl optionally substitutedwith 1, 2, or 3 groups independently selected from

[0111] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂ —R₁₀₅, or

[0112] R_(N) is —C(═O)—C₁-C₁₀ alkyl optionally substituted with 1, 2, or3 of halogen, —OH, —CO₂R₁₀₂, —C₁-C₆ thioalkoxy, —CO₂-phenyl,—NR₁₀₅R′₁₀₅, —SO₂—(C₁-C₈ alkyl), —C(═O)R₁₈₀, R₁₈₀, —CONR₁₀₅R′₁₀₅,—SO₂NR₁₀₅R′₁₀₅, —NH—CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀, —NH—CO—R₁₂₀,—NH—C(═O)—OH, —NH—C ═O)—OR, —NH—C(═O)—O-phenyl, —O—C(═O)—(C₁-C₆ alkyl),—O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl,—O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆haloalkoxy.

[0113] More preferred compounds of formula I-4 include compounds wherein

[0114] R_(N) is —C(═O)-phenyl, —C(═O)-oxazolyl, or —C(═O)-thiazolyl,where the ring portion of each is optionally substituted with 1 or 2groups independently selected from

[0115] C₁-C₆ alkyl, halogen, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, or

[0116] R_(N) is —C(═O)—C₁-C₁₀ alkyl optionally substituted with 1, 2, or3 of halogen, —OH, —NR₁₀₅R′₁₀₅, —SO₂—(C₁-C₈ alkyl), —C(═O)R₁₈₀, R₁₈₀,—CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅, —NH—CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀,—NH—CO—R₁₂₀, —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl,—O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl,—NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆ haloalkoxy.

[0117] Preferred compounds of the formula I-4 also include:

[0118] wherein R₁, R₁′, R_(N)′, R₁₁₀, R₁₂₀, R₁₀₅, and R′₁₀₅ are asdefined for formula I.

[0119] Other preferred compounds of formula I-1, I-2, I-3 and I-4include compounds of formula I-5, i.e., those of formula I-1, I-2, I-3or I-4 wherein

[0120] R_(N)′ is —C(═O)—(CRR′)₀₋₆R₁₀₀;

[0121] R₁₀₀ represents aryl, heteroaryl, heterocyclyl, -aryl-W-aryl,-aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl,-heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl,-heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl,-heterocyclyl-W-heterocyclyl, —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl, or—CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions ofeach are optionally substituted with 1, 2, or 3 groups independentlyselected from

[0122] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀—, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄ —(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,—(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂, —(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—O—R₁₅₀′—COOH,—(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, —(CH₂)₀₋₄—C₃-C₇cycloalkyl, (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or

[0123] R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅groups.

[0124] Preferred compounds of formula I—S include compounds wherein

[0125] R_(N)′ is —C(═O)—(CRR′)₀₋₆R₁₀₀; and

[0126] R₁₀₀ represents aryl, heteroaryl, heterocyclyl, where the ringportions of each are optionally substituted with 1, 2, or 3 groupsindependently selected from

[0127] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),—(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or

[0128] R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅groups.

[0129] Still more preferred compounds of formula I-5 include compoundswherein

[0130] R_(N)′ is —C(═O)—R₁₀₀; and

[0131] R₁₀₀ represents aryl or heteroaryl where the ring portions ofeach are optionally substituted with 1, 2, or 3 groups independentlyselected from

[0132] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—CO—NR₁₀₅R′105, —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′,—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,—(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—O—R₁₅₀′—COOH,—(CH₂)₀₋₄—S—(R₁₅₀), and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, or

[0133] R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅groups.

[0134] More preferred compounds of formula I-5 include compounds wherein

[0135] R_(N)′ is —C(═O)-aryl or —C(═O)-heteroaryl optionally substitutedwith 1, 2, or 3 groups independently selected from

[0136] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—₄—CO—NR₁₀₅R′₁₀₅, and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, or

[0137] R_(N)′ is —C(═O)—C₁-C₁₀ alkyl optionally substituted with 1, 2,or 3 of halogen, —OH, —CO₂R₁₀₂, —C₁-C₆thioalkoxy, —CO₂-phenyl,—NR₁₀₅R′₁₀₅, —SO₂—(C₁-C₈ alkyl), —C(═O)R₁₈₀, R₁₈₀, —CONR₁₀₅R′₁₀₅,—SO₂NR₁₀₅R′₁₀₅, —NH—CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀, —NH—CO—R₁₂₀,—NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl, —O—C(═O)—(C₁-C₆ alkyl),—O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl,—O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆haloalkoxy.

[0138] More preferred compounds of formula I-5 include compounds wherein

[0139] R_(N)′ is —C(═O)-phenyl optionally substituted with 1, 2, or 3groups independently selected from —OR, —NO₂, halogen, —C≡N, —OCF₃,—CF₃, or

[0140] R_(N)′ is —C(═O)—C₁-C₆ alkyl optionally substituted with 1, 2, or3 of halogen, —OH, —NR₁₀₅R′₁₀₅, —CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅,—NH—CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀, —NH—CO—R₁₂₀, —NH—C(═O)—OH,—NH—C(═O)—OR, —NH—C(═O)—O-phenyl, —O—C(═O)—(C₁-C₆ alkyl),—O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl,—O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆haloalkoxy.

[0141] Preferred compounds of the formula I-5 also include:

[0142] wherein R_(N), R₁, R₁′ and R₁₁₀ are as defined for formula I.

[0143] Other preferred compounds of formula I-5 include those of formulaI-6, i.e., compounds of formula I-5 wherein

[0144] R₂₀ at each occurrence is H;

[0145] R₁ is

[0146] C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, —S—(C₁-C₃)alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or

[0147] C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino;

[0148] R₁′ is —CH₂-phenyl where the phenyl ring is optionallysubstituted with 1, 2, 3, or 4 groups independently selected fromhalogen, C₁-C₄ alkoxy, hydroxy, —NO₂, and C₁-C₄ alkyl optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalogen, OH, SH, NH₂, NH(C₁-C₆ alkyl), N-(C₁-C₆ alkyl)(C₁-C₆ alkyl),C≡N, CF₃;

[0149] R_(N) and R_(N)′ are —C(═O)—(CRR′)₀₋₆R₁₀₀;

[0150] R₁₀₀ independently represents aryl, heteroaryl, heterocyclyl,-aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl,-heteroaryl-W-aryl, -heteroaryl-W-heteroaryl,-heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl,-heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl, or —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions of eachare optionally substituted with 1, 2, or 3 groups independently selectedfrom

[0151] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R−₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₃)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄ —R₁₄₀,—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),—(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or

[0152] R₁₀₀ independently is C₁-C₁₀ alkyl optionally substituted with 1,2, or 3 R₁₁₅ groups.

[0153] Preferred compounds of the formula I-6 include compounds of theformula I-7, i.e., compounds of the formula I-6 wherein:

[0154] R₂₀ at each occurrence is H;

[0155] R₁ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, —S—(C₁-C₃) alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino;

[0156] R₁′ is —CH₂-phenyl where the phenyl ring is optionallysubstituted with 1 or 2 groups independently selected from halogen,C₁-C₂ alkyl, C₁-C₂ alkoxy, hydroxy, —CF₃, and —NO₂;

[0157] R_(N) and R_(N)′ are —C(═O)—R₁₀₀; and

[0158] R₁₀₀ independently represents aryl or heteroaryl where the ringportions of each are optionally substituted with 1, 2, or 3 groupsindependently selected from

[0159] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′,—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—N (R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,—(CH₂)₀₋₄—NR₁₀₅R₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—O—R₁₅₀′—COOH,—(CH₂)₀₋₄—S—(R₁₅₀) and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, or

[0160] R₁₀₀ independently is C₁-C₁₀ alkyl optionally substituted with 1,2, or 3 R₁₁₅ groups.

[0161] Preferred compounds of the formula I-7 include compounds of theformula I-8, i.e., compounds of the formula I-7 wherein:

[0162] R₂₀ at each occurrence is H;

[0163] R₁ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from —SH, —C≡N, C₁-C₃ alkoxy, —S—(C₁-C₃)alkyl,amino, and mono- or dialkylamino;

[0164] R₁′ is —CH₂-phenyl where the phenyl ring is optionallysubstituted with 1 or 2 groups independently selected from halogen,C₁-C₂ alkyl, C₁-C₂ alkoxy, hydroxy, —CF₃, and —NO₂;

[0165] R_(N) is —C(═O)-phenyl, —C(═O)-oxazolyl, or —C(═O)-thiazolyl,where the ring portion of each is optionally substituted with 1 or 2groups independently selected from C₁-C₆ alkyl, halogen,—(CH₂)₀₋₄—CO—NR₁₀₅R′105, and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, or

[0166] R_(N) is —C(═O)—C₁-C₁₀ alkyl optionally substituted with 1, 2, or3 of halogen, —OH, —NR₁₀₅R′₁₀₅, —SO₂—(C₁-C₈ alkyl), —C(═O)R₁₈₀, R₁₈₀,—CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅—NH —CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀,—NH—CO—R₁₂₀, —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl,—O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl,—NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆ haloalkoxy; and

[0167] R_(N)′ is —C(═O)-phenyl optionally substituted with 1, 2, or 3groups independently selected from —OR, —NO₂, halogen, —C≡N, —OCF₃, and—CF₃, or

[0168] R_(N)′ is —C(═O)—C₁-C₆ alkyl optionally substituted with 1, 2, or3 of halogen, —OH, —NR₁₀₅R′₁₀₅, —CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅,—NH—CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀, —NH—CO—R₁₂₀, —NH—C(═O)—OH,—NH—C(═O)—OR, —NH—C(═O)—O—phenyl, —O—C(═O)—(C₁-C₆ alkyl),—O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl,—O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆haloalkoxy.

[0169] Preferred compounds of formula I-6 include compounds of formulaI-9:

[0170] wherein

[0171] A₃ and A₄ are independently hydrogen, halogen, C₁-C₄ alkoxy,hydroxy, —NO₂, and C₁-C₄ alkyl optionally substituted with 1, 2, or 3substituents independently selected from halogen, OH, SH, NH₂, NH(C₁-C₆alkyl), N—(C₁-C₆ alkyl)(C₁-C₆ alkyl), C≡N, CF₃;

[0172] R₁ is

[0173] C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, —S—(C₁-C₃) alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or

[0174] C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino;

[0175] R₁₀₀ represents aryl or heteroaryl where the ring portions ofeach are optionally substituted with 1, 2, or 3 groups independentlyselected from

[0176] —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′,—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,—(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—O—R₁₅₀′—COOH,—(CH₂)₀₋₄—S—(R₁₅₀), and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅, or

[0177] R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅groups;

[0178] R_(N)′ is —C(═O)-phenyl optionally substituted with 1, 2, or 3groups independently selected from —OR, —NO₂, halogen, —C≡N, —OCF₃, and—CF₃, or

[0179] R_(N)′ is —C(═O)—C₁-C₆ alkyl optionally substituted with 1, 2, or3 of halogen, —OH, —NR₁₀₅R′₁₀₅, —CONR₁₀₅R₁₁₀,—SO₂NR₁₀₅R′₁₀₅—NH—CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀, —NH—CO—R₁₂₀,—NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O—-phenyl, —O—C(═O)—(C₁-C₆ alkyl),—O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl,—O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆haloalkoxy.

[0180] Preferred compounds of formula I-9 include those of formulaI-9-a:

[0181] wherein

[0182] A₁ and A₂ are independently —OR, —NO₂, C₁-C₆ alkyl, halogen,—C≡N, —OCF₃, —CF₃, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀, —(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀,—(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₄₀,—(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅,—(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —-(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—O—R₁₅₀′—COOH,—(CH₂)₀₋₄—S—(R₁₅₀), and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅;

[0183] A₃ and A₄ are independently F, Cl, Br, I, OH, methyl, methoxy, orH; and

[0184] R₁ and R_(N)′ are as defined for formula I-9.

[0185] Preferred compounds of the formula I-9-a include those of formulaI-9-a′:

[0186] wherein A₂, A₃, A₄, R₁ and R_(N)′ are as defined for formulaI-9-a.

[0187] Also preferred compounds of formula I-9 include those of formulaI-9-b:

[0188] wherein

[0189] Q is O or S;

[0190] A₁ is —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′,—(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀, —(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₅₀,—(CH₂)₀₋₄—NR₁₀₅R′105, —(CH₂)₀₋₄—R₁₄₀, —(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl),—(CH₂)₀₋₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀), —(CH₂)₀₋₄—O—R₁₅₀′—COOH,—(CH₂)₀₋₄—S—(R₁₅₀), and —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅;

[0191] A₃ and A₄ are independently F, Cl, Br, I, OH, methyl, methoxy, orH; and

[0192] R₁ and R_(N)′ are as defined for formula I-9.

[0193] Also preferred compounds of formula I-9 include those of formulaI-9-c:

[0194] wherein

[0195] R₁, R_(N)′, A₃ and A₄ are is defined for formula I-9-b.

[0196] Other compounds of the formula I-9 include those of formulaI-9-d:

[0197] wherein R₁, R_(N)′, R₁₀₀, A₃ and A₄ are as defined for formulaI-9.

[0198] In the compounds of the invention, it is preferred that R₁ andR₁′ are not simultaneously benzyl. Thus, preferred compounds of theformula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8 and I-9 include thosewherein R₁ and R₁′ are not simultaneously benzyl.

[0199] In the compounds of the invention, it is preferred that R_(N) orR_(N)′ are not an alpha amino acid. Thus, preferred compounds of theformula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8 and I-9 include thosewherein R_(N) or R_(N)′ are not an alpha amino acid. By alpha amino acidis meant alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutaminic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine and valine.

[0200] In another aspect, the invention provides intermediates of theformula X:

[0201] wherein

[0202] Pg is an amine protecting group; and

[0203] R₁ and R₁′ are as defined above.

[0204] The invention further provides intermediates of the formula XI:

[0205] wherein

[0206] Pg is an amine protecting group; and

[0207] R₁ and R₁′ are as defined above.

[0208] The invention also provides intermediates of the formula A:

[0209] wherein

[0210] Pg is an amine protecting group; and

[0211] R₁ is as defined above.

[0212] The invention further provides intermediates of the formula B:

[0213] wherein

[0214] Pg is an amine protecting group; and

[0215] R₁ and R₂₀ are as defined above.

[0216] The invention also provides intermediates of the formulae XII andXIII:

[0217] wherein

[0218] Pg and Pg₂ are amine protecting groups; and

[0219] R₁, R₁′ and R₂₀ are as defined above.

[0220] The invention also provides methods for treating a patient whohas, or in preventing a patient from getting, a disease or conditionselected from the group consisting of Alzheimer's disease, for helpingprevent or delay the onset of Alzheimer's disease, for treating patientswith mild cognitive impairment (MCI) and preventing or delaying theonset of Alzheimer's disease in those who would progress from MCI to AD,for treating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, or diffuse Lewy body typeof Alzheimer's disease and who is in need of such treatment whichincludes administration of a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salts thereof.

[0221] In an embodiment, this method of treatment can be used where thedisease is Alzheimer's disease.

[0222] In an embodiment, this method of treatment can help prevent ordelay the onset of Alzheimer's disease.

[0223] In an embodiment, this method of treatment can be used where thedisease is mild cognitive impairment.

[0224] In an embodiment, this method of treatment can be used where thedisease is Down's syndrome.

[0225] In an embodiment, this method of treatment can be used where thedisease is Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type.

[0226] In an embodiment, this method of treatment can be used where thedisease is cerebral amyloid angiopathy.

[0227] In an embodiment, this method of treatment can be used where thedisease is degenerative dementias.

[0228] In an embodiment, this method of treatment can be used where thedisease is diffuse Lewy body type of Alzheimer's disease.

[0229] In an embodiment, this method of treatment can treat an existingdisease.

[0230] In an embodiment, this method of treatment can prevent a diseasefrom developing.

[0231] In an embodiment, this method of treatment can employtherapeutically effective amounts: for oral administration from about0.1 mg/day to about 1,000 mg/day; for parenteral, sublingual,intranasal, intrathecal administration from about 0.5 to about 100mg/day; for depo administration and implants from about 0.5 mg/day toabout 50 mg/day; for topical administration from about 0.5 mg/day toabout 200 mg/day; for rectal administration from about 0.5 mg to about500 mg.

[0232] In an embodiment, this method of treatment can employtherapeutically effective amounts: for oral administration from about 1mg/day to about 100 mg/day; and for parenteral administration from about5 to about 50 mg daily.

[0233] In an embodiment, this method of treatment can employtherapeutically effective amounts for oral administration from about 5mg/day to about 50 mg/day.

[0234] The invention also includes pharmaceutical compositions whichinclude a compound of formula (I) or a pharmaceutically acceptable saltsthereof.

[0235] The invention also includes the use of a compound of formula (I)or pharmaceutically acceptable salts thereof for the manufacture of amedicament for use in treating a patient who has, or in preventing apatient from getting, a disease or condition selected from the groupconsisting of Alzheimei's disease, for helping prevent or delay theonset of Alzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease and who isin need of such treatment.

[0236] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is Alzheimer's disease.

[0237] In an embodiment, this use of a compound of formula (I) can helpprevent or delay the onset of Alzheimer's disease.

[0238] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is mild cognitive impairment.

[0239] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is Down's syndrome.

[0240] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is Hereditary Cerebral Hemorrhage withAmyloidosis of the Dutch-Type.

[0241] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is cerebral amyloid angiopathy.

[0242] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is degenerative dementias.

[0243] In an embodiment, this use of a compound of formula (I) can beemployed where the disease is diffuse Lewy body type of Alzheimer'sdisease.

[0244] In an embodiment, this use of a compound employs apharmaceutically acceptable salt selected from the group consisting ofsalts of the following acids hydrochloric, hydrobromic, hydroiodic,nitric, sulfuric, phosphoric, citric, methanesulfonic,CH₃—(CH₂)_(n)—COOH where n is 0 thru 4, HOOC—(CH₂)_(n)—COOH where n isas defined above, HOOC—CH═CH—COOH, and phenyl-COOH.

[0245] The invention also includes methods for inhibiting beta-secretaseactivity, for inhibiting cleavage of amyloid precursor protein (APP), ina reaction mixture, at a site between Met596 and Asp597, numbered forthe APP-695 amino acid isotype, or at a corresponding site of an isotypeor mutant thereof; for inhibiting production of amyloid beta peptide (Abeta) in a cell; for inhibiting the production of beta-amyloid plaque inan animal; and for treating or preventing a disease characterized bybeta-amyloid deposits in the brain. These methods each includeadministration of a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salts thereof.

[0246] The invention also includes a method for inhibitingbeta-secretase activity, including exposing said beta-secretase to aneffective inhibitory amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

[0247] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of less than 50micromolar.

[0248] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 micromolar orless.

[0249] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 1 micromolar or less.

[0250] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 nanomolar or less.

[0251] In an embodiment, this method includes exposing saidbeta-secretase to said compound in vitro.

[0252] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a cell.

[0253] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a cell in an animal.

[0254] In an embodiment, this method includes exposing saidbeta-secretase to said compound in a human.

[0255] The invention also includes a method for inhibiting cleavage ofamyloid precursor protein (APP), in a reaction mixture, at a sitebetween Met596 and Asp597, numbered for the APP-695 amino acid isotype;or at a corresponding site of an isotype or mutant thereof, includingexposing said reaction mixture to an effective inhibitory amount of acompound of formula (I), or a pharmaceutically acceptable salt thereof.

[0256] In an embodiment, this method employs a cleavage site: betweenMet652 and Asp653, numbered for the APP-751 isotype; between Met 671 andAsp 672, numbered for the APP-770 isotype; between Leu596 and Asp597 ofthe APP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751Swedish Mutation; or between Leu671 and Asp672 of the APP-770 SwedishMutation.

[0257] In an embodiment, this method exposes said reaction mixture invitro.

[0258] In an embodiment, this method exposes said reaction mixture in acell.

[0259] In an embodiment, this method exposes said reaction mixture in ananimal cell.

[0260] In an embodiment, this method exposes said reaction mixture in ahuman cell.

[0261] The invention also includes a method for inhibiting production ofamyloid beta peptide (A beta) in a cell, including administering to saidcell an effective inhibitory amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

[0262] In an embodiment, this method includes administering to ananimal.

[0263] In an embodiment, this method includes administering to a human.

[0264] The invention also includes a method for inhibiting theproduction of beta-amyloid plaque in an animal, including administeringto said animal an effective inhibitory amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof.

[0265] In an embodiment, this method includes administering to a human.

[0266] The invention also includes a method for treating or preventing adisease characterized by beta-amyloid deposits in the brain includingadministering to a patient an effective therapeutic amount of a compoundof formula (I), or a pharmaceutically acceptable salt thereof.

[0267] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of less than 50micromolar.

[0268] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 micromolar orless.

[0269] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 1 micromolar or less.

[0270] In an embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 nanomolar or less.

[0271] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 0.1 to about 1000 mg/day.

[0272] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 15 to about 1500 mg/day.

[0273] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 1 to about 100 mg/day.

[0274] In an embodiment, this method employs a compound at a therapeuticamount in the range of from about 5 to about 50 mg/day.

[0275] In an embodiment, this method can be used where said disease isAlzheimer's disease.

[0276] In an embodiment, this method can be used where said disease isMild Cognitive Impairment, Down's Syndrome, or Hereditary CerebralHemorrhage with Amyloidosis of the Dutch Type.

[0277] The invention also includes a composition includingbeta-secretase complexed with a compound of formula (I), or apharmaceutically acceptable salt thereof.

[0278] The invention also includes a method for producing abeta-secretase complex including exposing beta-secretase to a compoundof formula (I), or a pharmaceutically acceptable salt thereof, in areaction mixture under conditions suitable for the production of saidcomplex.

[0279] In an embodiment, this method employs exposing in vitro.

[0280] In an embodiment, this method employs a reaction mixture that isa cell.

[0281] The invention also includes a component kit including componentparts capable of being assembled, in which at least one component partincludes a compound of formula I enclosed in a container.

[0282] In an embodiment, this component kit includes lyophilizedcompound, and at least one further component part includes a diluent.

[0283] The invention also includes a container kit including a pluralityof containers, each container including one or more unit dose of acompound of formula (I):, or a pharmaceutically acceptable salt thereof.

[0284] In an embodiment, this container kit includes each containeradapted for oral delivery and includes a tablet, gel, or capsule.

[0285] In an embodiment, this container kit includes each containeradapted for parenteral delivery and includes a depot product, syringe,ampoule, or vial.

[0286] In an embodiment, this container kit includes each containeradapted for topical delivery and includes a patch, medipad, ointment, orcream.

[0287] The invention also includes an agent kit including a compound offormula (I), or a pharmaceutically acceptable salt thereof; and one ormore therapeutic agent selected from the group consisting of anantioxidant, an anti-inflammatory, a gamma secretase inhibitor, aneurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an Abeta peptide, and an anti-A beta antibody.

[0288] The invention also includes a composition including a compound offormula (I), or a pharmaceutically acceptable salt thereof; and an inertdiluent or edible carrier.

[0289] In an embodiment, this composition includes a carrier that is anoil.

[0290] The invention also includes a composition including: a compoundof formula (I), or a pharmaceutically acceptable salt thereof; and abinder, excipient, disintegrating agent, lubricant, or gildant.

[0291] The invention also includes a composition including a compound offormula (I), or a pharmaceutically acceptable salt thereof; disposed ina cream, ointment, or patch.

[0292] The invention provides compounds of formula (I) that are usefulin treating and preventing Alzheimer's disease. The compounds of theinvention can be prepared by one skilled in the art based only onknowledge of the compound's chemical structure. The chemistry for thepreparation of the compounds of this invention is known to those skilledin the art. In fact, there is more than one process to prepare thecompounds of the invention. Specific examples of methods of preparationcan be found in the art. For examples, see J. Org. Chem. 1998, 63,4898-4906; J. Org. Chem. 1997, 62, 9348-9353; J. Org. Chem. 1996, 61,5528-5531; J. Med. Chem. 1993, 36, 320-330; J. Am. Chem. Soc. 1999, 121,1145-1155; and references cited therein. See also U.S. Pat. Nos.6,150,530, 5,892,052, 5,696,270, and 5,362,912, which are incorporatedherein by reference, and references cited therein.

[0293] Examples of various processes that can be used to prepare thecompounds of the invention are set forth in CHART I.

[0294] Process 1: (R₂₀═H) A suitably protected ester is converted to aHorner-Emmons reagent and is reacted with an aldehyde generating aα,β-unsaturated ketone. Reduction to the alcohol is followed by anepoxidation. Reaction of the epoxide with a nitrogen nucleophile givesthe free amine, which can be coupled with R_(N). Deprotection by knownmethods provides the amine that is condensed with a R_(N)′ which maybethe same or different from R_(N). In addition, R₁ and R₁′ may or may notbe equivalent. See J. Org. Chem. 1996, 61, 2901—, J. Org. Chem. 1997,62, 9348-9353, Tetrahedron Lett. 1987, 28, 611—

Process 2

[0295]

[0296] Process 2 (R₂₀═H): An N-protected α-amino aldehyde (intermediateA) is synthesized from known α-amino acid or their derivatives throughmethods known in the art (for a review see: Chem. Rev. 1989, 89, 149).Pg=Protecting group; for examples see Wuts & Green, Protective Groups inOrganic Synthesis. 1st -3rd Ed.

Process 3

[0297]

[0298] Process 3 (R₂₀ does not equal H): An N-protected α-amino aldehyde(intermediate B) is synthesized from known a-amino acid or therederivatives through methods known in the art (for a review see: Chem.Rev. 1989, 89, 149).

Process 4 (Symmetrical Substitution)

[0299]

[0300] Process 4: Intermediate A or B is reacted with an aldehyde in aPinacol reaction to give the diol. In this case symmetricallysubstituted compounds are obtained (i.e., R₁ and R₁′ are the same andboth R₂₀s are the same). This reaction is catalyzed by vanadium andtitanium salts and is known in the art (see J. Am. Chem. Soc. 1989, 111,8014-8016, J. Org. Chem. 1990, 55, 4506-4508, J. Org. Chem. 1996, 61,5528-5531, J. Org. Chem. 1992, 57, 28-32, J. Med. Chem. 1990, 33,2687-2689, J. Am. Chem. Soc. 1999, 121, 1145-1155). Deprotection byknown methods provides the amine that is condensed with carboxylic acidto give the final compounds.

Process 5 (Unsymmetrically Substituted)

[0301]

[0302] Process 5: Intermediate A or B is reacted with an aldehyde inwhich a different protecting group is employed in a Pinacol reaction togive the unsymmetrically protected diol. In this case R₁ and R₁′ may ormay not be equivalent. This reaction is catalyzed by vanadium andtitanium salts and is known in the art (see J. Am. Chem. Soc. 1989, 111,8014-8016, J. Org. Chem. 1990, 55, 4506-4508, J. Org. Chem. 1996, 61,5528-5531, J. Org. Chem. 1992, 57, 28-32, J. Med. Chem. 1990, 33,2687-2689, J. Am. Chem. Soc. 1999, 121, 1145-1155). Deprotection byknown methods provides the amine that is reacted with R_(N) to give theintermediate that is subjected to a second deprotection and couplingwith R_(N). With this sequence, different substitution patterns areprepared when the R_(N), R₂ and R₁ substituents are dissimilar.

[0303] See also WO 92/00948 for alternative methods of synthesis.

[0304] The protection of amines is conducted, where appropriate, bymethods known to those skilled in the art. Amino protecting groups areknown to those skilled in the art. See for example, “Protecting Groupsin Organic Synthesis”, John Wiley and sons, New York, N.Y., 1981,Chapter 7; “Protecting Groups in Organic Chemistry”, Plenum Press, NewYork, N.Y., 1973, Chapter 2. When the amino protecting group is nolonger needed, it is removed by methods known to those skilled in theart. By definition the amino protecting group must be readily removable.A variety of suitable methodologies are known ro those skilled in theart; see also T. W. Green and P. G. M. Wuts in “Protective Groups inOrganic Chemistry, John Wiley and Sons, 1991. Suitable amino protectinggroups include t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl,phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl,4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobrornyloxycarbonyl, 1-piperidyloxycarbonyl, 9-fluoroenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H.

[0305] It is preferred that the protecting group be t-butoxycarbonyl(BOC) and/or benzyloxycarbonyl (CBZ), it is more preferred that theprotecting group be t-butoxycarbonyl. One skilled in the art willrecognize suitable methods of introducing a t-butoxycarbonyl orbenzyloxycarbonyl protecting group and may additionally consult T. W.Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry, JohnWiley and Sons, 1991 for guidance.

[0306] The compounds of the invention may contain geometric or opticalisomers as as tautomers. Thus, the invention includes all tautomers andpure geometric isomers, such as the E and Z geometric isomers, as asmixtures thereof. Further, the invention includes pure enantiomers anddiastereomers as as mixtures thereof, including racemic mixtures. Theindividual geometric isomers, enantiomers or diastereomers may beprepared or isolated by methods known to those skilled in the art,including but not limited to chiral chromatography; preparingdiastereomers, separating the diastereomers and converting thediastereomers into enantiomers through the use of a chiral resolvingagent.

[0307] Compounds of the invention with designated stereochemistry can beincluded in mixtures, including racemic mixtures, with otherenantiomers, diastereomers, geometric isomers or tautomers. In apreferred aspect, compounds of the invention with (S, R, R), (S, S, S),or (S, R, S) stereochemistry are typically present in these mixtures inexcess of 50 percent. Preferably, compounds of the invention withdesignated stereochemistry are present in these mixtures in excess of 80percent. More preferably, compounds of the invention with designatedstereochemistry are present in these mixtures in excess of 90 percent.Even more preferably, compounds of the invention with designatedstereochemistry are present in these mixtures in excess of 99 percent.

[0308] Several of the compounds of formula (I) are amines, and as suchform salts when reacted with acids. Pharmaceutically acceptable saltsare preferred over the corresponding amines of formula (I) since theyproduce compounds which are more water soluble, stable and/or morecrystalline. Pharmaceutically acceptable salts are any salt whichretains the activity of the parent compound and does not impart anydeleterious or undesirable effect on the subject to whom it isadministered and in the context in which it is administered.Pharmaceutically acceptable salts include salts of both inorganic andorganic acids. The preferred pharmaceutically acceptable salts includesalts of the following acids acetic, aspartic, benzenesulfonic, benzoic,bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic,carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl,esylic, formic, fumaric, gluceptic, gluconic, glutamic,glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic,lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, phthalic, polygalactouronic,propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic,sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic. Forother acceptable salts, see Int. J. Pharm., 33, 201-217 (1986) and J.Pharm. Sci., 66(1), 1, (1977).

[0309] The invention provides compounds, compositions, kits, and methodsfor inhibiting beta-secretase enzyme activity and A beta peptideproduction. Inhibition of beta-secretase enzyme activity halts orreduces the production of A beta from APP and reduces or eliminates theformation of beta-amyloid deposits in the brain.

[0310] Methods of the Invention

[0311] The compounds of the invention, and pharmaceutically acceptablesalts thereof, are useful for treating humans or animals suffering froma condition characterized by a pathological form of beta-amyloidpeptide, such as beta-amyloid plaques, and for helping to prevent ordelay the onset of such a condition. For example, the compounds areuseful for treating Alzheimer's disease, for helping prevent or delaythe onset of Alzheimer's disease, for treating patients with MCI (mildcognitive impairment) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobal hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, and diffuse Lewy body typeAlzheimer's disease. The compounds and compositions of the invention areparticularly useful for treating or preventing Alzheimer's disease. Whentreating or preventing these diseases, the compounds of the inventioncan either be used individually or in combination, as is best for thepatient.

[0312] As used herein, the term “treating” means that the compounds ofthe invention can be used in humans with at least a tentative diagnosisof disease. The compounds of the invention will delay or slow theprogression of the disease thereby giving the individual a more usefullife span.

[0313] The term “preventing” means that the compounds of the inventionare useful when administered to a patient who has not been diagnosed aspossibly having the disease at the time of administration, but who wouldnormally be expected to develop the disease or be at increased risk forthe disease. The compounds of the invention will slow the development ofdisease symptoms, delay the onset of the disease, or prevent theindividual from developing the disease at all. Preventing also includesadministration of the compounds of the invention to those individualsthought to be predisposed to the disease due to age, familial history,genetic or chromosomal abnormalities, and/or due to the presence of oneor more biological markers for the disease, such as a known geneticmutation of APP or APP cleavage products in brain tissues or fluids.

[0314] In treating or preventing the above diseases, the compounds ofthe invention are administered in a therapeutically effective amount.The therapeutically effective amount will vary depending on theparticular compound used and the route of administration, as is known tothose skilled in the art.

[0315] In treating a patient displaying any of the diagnosed aboveconditions a physician may administer a compound of the inventionimmediately and continue administration indefinitely, as needed. Intreating patients who are not diagnosed as having Alzheimer's disease,but who are believed to be at substantial risk for Alzheimer's disease,the physician should preferably start treatment when the patient firstexperiences early pre-Alzheimer's symptoms such as, memory or cognitiveproblems associated with aging. In addition, there are some patients whomay be determined to be at risk for developing Alzheimer's through thedetection of a genetic marker such as APOE4 or other biologicalindicators that are predictive for Alzheimer's disease. In thesesituations, even though the patient does not have symptoms of thedisease, administration of the compounds of the invention may be startedbefore symptoms appear, and treatment may be continued indefinitely toprevent or delay the onset of the disease.

[0316] Dosage Forms and Amounts

[0317] The compounds of the invention can be administered orally,parenterally, (IV, IM, depo-IM, SQ, and depo SQ), sublingually,intranasally (inhalation), intrathecally, topically, or rectally. Dosageforms known to those of skill in the art are suitable for delivery ofthe compounds of the invention.

[0318] Compositions are provided that contain therapeutically effectiveamounts of the compounds of the invention. The compounds are preferablyformulated into suitable pharmaceutical preparations such as tablets,capsules, or elixirs for oral administration or in sterile solutions orsuspensions for parenteral administration. Typically the compoundsdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art.

[0319] About 1 to 500 mg of a compound or mixture of compounds of theinvention or a physiologically acceptable salt or ester is compoundedwith a physiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein those compositions or preparations is such that a suitable dosage inthe range indicated is obtained. The compositions are preferablyformulated in a unit dosage form, each dosage containing from about 2 toabout 100 mg, more preferably about 10 to about 30 mg of the activeingredient. The term “unit dosage from” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

[0320] To prepare compositions, one or more compounds of the inventionare mixed with a suitable pharmaceutically acceptable carrier. Uponmixing or addition of the compound(s), the resulting mixture may be asolution, suspension, emulsion, or the like. Liposomal suspensions mayalso be suitable as pharmaceutically acceptable carriers. These may beprepared according to methods known to those skilled in the art. Theform of the resulting mixture depends upon a number of factors,including the intended mode of administration and the solubility of thecompound in the selected carrier or vehicle. The effective concentrationis sufficient for lessening or ameliorating at least one symptom of thedisease, disorder, or condition treated and may be empiricallydetermined.

[0321] Pharmaceutical carriers or vehicles suitable for administrationof the compounds provided herein include any such carriers known tothose skilled in the art to be suitable for the particular mode ofadministration. In addition, the active materials can also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, or have another action.The compounds may be formulated as the sole pharmaceutically activeingredient in the composition or may be combined with other activeingredients.

[0322] Where the compounds exhibit insufficient solubility, methods forsolubilizing may be used. Such methods are known and include, but arenot limited to, using cosolvents such as dimethylsulfoxide (DMSO), usingsurfactants such as Tween®, and dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as salts or prodrugs mayalso be used in formulating effective pharmaceutical compositions.

[0323] The concentration of the compound is effective for delivery of anamount upon administration that lessens or ameliorates at least onesymptom of the disorder for which the compound is administered.Typically, the compositions are formulated for single dosageadministration.

[0324] The compounds of the invention may be prepared with carriers thatprotect them against rapid elimination from the body, such astime-release formulations or coatings. Such carriers include controlledrelease formulations, such as, but not limited to, microencapsulateddelivery systems. The active compound is included in thepharmaceutically acceptable carrier in an amount sufficient to exert atherapeutically useful effect in the absence of undesirable side effectson the patient treated. The therapeutically effective concentration maybe determined empirically by testing the compounds in known in vitro andin vivo model systems for the treated disorder.

[0325] The compounds and compositions of the invention can be enclosedin multiple or single dose containers. The enclosed compounds andcompositions can be provided in kits, for example, including componentparts that can be assembled for use. For example, a compound inhibitorin lyophilized form and a suitable diluent may be provided as separatedcomponents for combination prior to use. A kit may include a compoundinhibitor and a second therapeutic agent for co-administration. Theinhibitor and second therapeutic agent may be provided as separatecomponent parts. A kit may include a plurality of containers, eachcontainer holding one or more unit dose of the compound of theinvention. The containers are preferably adapted for the desired mode ofadministration, including, but not limited to tablets, gel capsules,sustained-release capsules, and the like for oral administration; depotproducts, pre-filled syringes, ampoules, vials, and the like forparenteral administration; and patches, medipads, creams, and the likefor topical administration.

[0326] The concentration of active compound in the drug composition willdepend on absorption, inactivation, and excretion rates of the activecompound, the dosage schedule, and amount administered as well as otherfactors known to those of skill in the art.

[0327] The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the disease being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

[0328] If oral administration is desired, the compound should beprovided in a composition that protects it from the acidic environmentof the stomach. For example, the composition can be formulated in anenteric coating that maintains its integrity in the stomach and releasesthe active compound in the intestine. The composition may also beformulated in combination with an antacid or other such ingredient.

[0329] Oral compositions will generally include an inert diluent or anedible carrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules, or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

[0330] The tablets, pills, capsules, troches, and the like can containany of the following ingredients or compounds of a similar nature: abinder such as, but not limited to, gum tragacanth, acacia, corn starch,or gelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a gildant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

[0331] When the dosage unit form is a capsule, it can contain, inaddition to material of the above type, a liquid carrier such as a fattyoil. In addition, dosage unit forms can contain various other materials,which modify the physical form of the dosage unit, for example, coatingsof sugar and other enteric agents. The compounds can also beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings, and flavors.

[0332] The active materials can also be mixed with other activematerials that do not impair the desired action, or with materials thatsupplement the desired action.

[0333] Solutions or suspensions used for parenteral, intradermal,subcutaneous, or topical application can include any of the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oil, a naturally occurring vegetable oil such as sesameoil, coconut oil, peanut oil, cottonseed oil, and the like, or asynthetic fatty vehicle such as ethyl oleate, and the like, polyethyleneglycol, glycerine, propylene glycol, or other synthetic solvent;antimicrobial agents such as benzyl alcohol and methyl parabens;antioxidants such as ascorbic acid and sodium bisulfite; chelatingagents such as ethylenediaminetetraacetic acid (EDTA); buffers such asacetates, citrates, and phosphates; and agents for the adjustment oftonicity such as sodium chloride and dextrose. Parenteral preparationscan be enclosed in ampoules, disposable syringes, or multiple dose vialsmade of glass, plastic, or other suitable material. Buffers,preservatives, antioxidants, and the like can be incorporated asrequired.

[0334] Where administered intravenously, suitable carriers includephysiological saline, phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents such as glucose,polyethylene glycol, polypropyleneglycol, and mixtures thereof.Liposomal suspensions including tissue-targeted liposomes may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known for example, as described in U.S. Pat. No.4,522,811.

[0335] The active compounds may be prepared with carriers that protectthe compound against rapid elimination from the body, such astime-release formulations or coatings. Such carriers include controlledrelease formulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid, and the like.Methods for preparation of such formulations are known to those skilledin the art.

[0336] The compounds of the invention can be administered orally,parenterally (IV, IM, depo-IM, SQ, and depo-SQ), sublingually,intranasally (inhalation), intrathecally, topically, or rectally. Dosageforms known to those skilled in the art are suitable for delivery of thecompounds of the invention.

[0337] Compounds of the invention may be administered enterally orparenterally. When administered orally, compounds of the invention canbe administered in usual dosage forms for oral administration as is wellknown to those skilled in the art. These dosage forms include the usualsolid unit dosage forms of tablets and capsules as well as liquid dosageforms such as solutions, suspensions, and elixirs. When the solid dosageforms are used, it is preferred that they be of the sustained releasetype so that the compounds of the invention need to be administered onlyonce or twice daily.

[0338] The oral dosage forms are administered to the patient 1, 2, 3, or4 times daily. It is preferred that the compounds of the invention beadministered either three or fewer times, more preferably once or twicedaily. Hence, it is preferred that the compounds of the invention beadministered in oral dosage form. It is preferred that whatever oraldosage form is used, that it be designed so as to protect the compoundsof the invention from the acidic environment of the stomach. Entericcoated tablets are well known to those skilled in the art. In addition,capsules filled with small spheres each coated to protect from theacidic stomach, are also well known to those skilled in the art.

[0339] When administered orally, an administered amount therapeuticallyeffective to inhibit beta-secretase activity, to inhibit A betaproduction, to inhibit A beta deposition, or to treat or prevent AD isfrom about 0.1 mg/day to about 1,000 mg/day. It is preferred that theoral dosage is from about 1 mg/day to about 100 mg/day. It is morepreferred that the oral dosage is from about 5 mg/day to about 50mg/day. It is understood that while a patient may be started at onedose, that dose may be varied over time as the patient's conditionchanges.

[0340] Compounds of the invention may also be advantageously deliveredin a nano crystal dispersion formulation. Preparation of suchformulations is described, for example, in U.S. Pat. No. 5,145,684. Nanocrystalline dispersions of HIV protease inhibitors and their method ofuse are described in U.S. Pat. No. 6,045,829. The nano crystallineformulations typically afford greater bioavailability of drug compounds.

[0341] The compounds of the invention can be administered parenterally,for example, by IV, IM, depo-IM, SC, or depo-SC. When administeredparenterally, a therapeutically effective amount of about 0.5 to about100 mg/day, preferably from about 5 to about 50 mg daily should bedelivered. When a depot formulation is used for injection once a monthor once every two weeks, the dose should be about 0.5 mg/day to about 50mg/day, or a monthly dose of from about 15 mg to about 1,500 mg. In partbecause of the forgetfulness of the patients with Alzheimer's disease,it is preferred that the parenteral dosage form be a depo formulation.

[0342] The compounds of the invention can be administered sublingually.When given sublingually, the compounds of the invention should be givenone to four times daily in the amounts described above for IMadministration.

[0343] The compounds of the invention can be administered intranasally.When given by this route, the appropriate dosage forms are a nasal sprayor dry powder, as is known to those skilled in the art. The dosage ofthe compounds of the invention for intranasal administration is theamount described above for IM administration.

[0344] The compounds of the invention can be administered intrathecally.When given by this route the appropriate dosage form can be a parenteraldosage form as is known to those skilled in the art. The dosage of thecompounds of the invention for intrathecal administration is the amountdescribed above for IM administration.

[0345] The compounds of the invention can be administered topically.When given by this route, the appropriate dosage form is a cream,ointment, or patch. Because of the amount of the compounds of theinvention to be administered, the patch is preferred. When administeredtopically, the dosage is from about 0.5 mg/day to about 200 mg/day.Because the amount that can be delivered by a patch is limited, two ormore patches may be used. The number and size of the patch is notimportant, what is important is that a therapeutically effective amountof the compounds of the invention be delivered as is known to thoseskilled in the art. The compounds of the invention can be administeredrectally by suppository as is known to those skilled in the art. Whenadministered by suppository, the therapeutically effective amount isfrom about 0.5 mg to about 500 mg.

[0346] The compounds of the invention can be administered by implants asis known to those skilled in the art. When administering a compound ofthe invention by implant, the therapeutically effective amount is theamount described above for depot administration.

[0347] Given a particular compound of the invention and a desired dosageform, one skilled in the art would know how to prepare and administerthe appropriate dosage form.

[0348] The compounds of the invention are used in the same manner, bythe same routes of administration, using the same pharmaceutical dosageforms, and at the same dosing schedule as described above, forpreventing disease or treating patients with MCI (mild cognitiveimpairment) and preventing or delaying the onset of Alzheimer's diseasein those who would progress from MCI to AD, for treating or preventingDown's syndrome, for treating humans who have Hereditary CerebralHemorrhage with Amyloidosis of the Dutch-Type, for treating cerebralamyloid angiopathy and preventing its potential consequences, i.e.single and recurrent lobar hemorrhages, for treating other degenerativedementias, including dementias of mixed vascular and degenerativeorigin, dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, and diffuse Lewy body type of Alzheimer'sdisease.

[0349] The compounds of the invention can be used in combination, witheach other or with other therapeutic agents or approaches used to treator prevent the conditions listed above. Such agents or approachesinclude: acetylcholine esterase inhibitors such as tacrine(tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride,(marketed as Aricept® and rivastigmine (marketed as Exelon®);gamma-secretase inhibitors; anti-inflammatory agents such ascyclooxygenase II inhibitors; anti-oxidants such as Vitamin E andginkolides; immunological approaches, such as, for example, immunizationwith A beta peptide or administration of anti-A beta peptide antibodies;statins; and direct or indirect neurotropic agents such asCerebrolysin®, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and otherneurotropic agents of the future.

[0350] In addition, the compounds of formula (I) can also be used withinhibitors of P-glycoprotein (P-gp). P-gp inhibitors and the use of suchcompounds are known to those skilled in the art. See for example, CancerResearch, 53, 4595-4602 (1993), Clin. Cancer Res., 2, 7-12 (1996),Cancer Research, 56, 4171-4179 (1996), International PublicationsWO99/64001 and WO01/10387. The important thing is that the blood levelof the P-gp inhibitor be such that it exerts its effect in inhibitingP-gp from decreasing brain blood levels of the compounds of formula (A).To that end the P-gp inhibitor and the compounds of formula (A) can beadministered at the same time, by the same or different route ofadministration, or at different times. The important thing is not thetime of administration but having an effective blood level of the P-gpinhibitor.

[0351] Suitable P-gp inhibitors include cyclosporin A, verapamil,tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate,progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines,acridine derivatives such as GF120918, FK506, VX-710, LY335979, PSC-833,GF-102,918 and other steroids. It is to be understood that additionalagents will be found that have the same function and therefore achievethe same outcome; such compounds are also considered to be useful.

[0352] The P-gp inhibitors can be administered orally, parenterally,(IV, IM, IM-depo, SQ, SQ-depo), topically, sublingually, rectally,intranasally, intrathecally and by implant.

[0353] The therapeutically effective amount of the P-gp inhibitors isfrom about 0.1 to about 300 mg/kg/day, preferably about 0.1 to about 150mg/kg daily. It is understood that while a patient may be started on onedose, that dose may have to be varied over time as the patient'scondition changes.

[0354] When administered orally, the P-gp inhibitors can be administeredin usual dosage forms for oral administration as is known to thoseskilled in the art. These dosage forms include the usual solid unitdosage forms of tablets and capsules as well as liquid dosage forms suchas solutions, suspensions and elixirs. When the solid dosage forms areused, it is preferred that they be of the sustained release type so thatthe P-gp inhibitors need to be administered only once or twice daily.The oral dosage forms are administered to the patient one thru fourtimes daily. It is preferred that the P-gp inhibitors be administeredeither three or fewer times a day, more preferably once or twice daily.Hence, it is preferred that the P-gp inhibitors be administered in soliddosage form and further it is preferred that the solid dosage form be asustained release form which permits once or twice daily dosing. It ispreferred that what ever dosage form is used, that it be designed so asto protect the P-gp inhibitors from the acidic environment of thestomach. Enteric coated tablets are well known to those skilled in theart. In addition, capsules filled with small spheres each coated toprotect from the acidic stomach, are also well known to those skilled inthe art.

[0355] In addition, the P-gp inhibitors can be administeredparenterally. When administered parenterally they can be administeredIV, IM, depo-IM, SQ or depo-SQ.

[0356] The P-gp inhibitors can be given sublingually. When givensublingually, the P-gp inhibitors should be given one thru four timesdaily in the same amount as for IM administration.

[0357] The P-gp inhibitors can be given intranasally. When given by thisroute of administration, the appropriate dosage forms are a nasal sprayor dry powder as is known to those skilled in the art. The dosage of theP-gp inhibitors for intranasal administration is the same as for IMadministration.

[0358] The P-gp inhibitors can be given intrathecally. When given bythis route of administration the appropriate dosage form can be aparenteral dosage form as is known to those skilled in the art.

[0359] The P-gp inhibitors can be given topically. When given by thisroute of administration, the appropriate dosage form is a cream,ointment or patch. Because of the amount of the P-gp inhibitors neededto be administered the patch is preferred. However, the amount that canbe delivered by a patch is limited. Therefore, two or more patches maybe required. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the P-gpinhibitors be delivered as is known to those skilled in the art.

[0360] The P-gp inhibitors can be administered rectally by suppositoryas is known to those skilled in the art.

[0361] The P-gp inhibitors can be administered by implants as is knownto those skilled in the art.

[0362] There is nothing novel about the route of administration nor thedosage forms for administering the P-gp inhibitors. Given a particularP-gp inhibitor, and a desired dosage form, one skilled in the art wouldknow how to prepare the appropriate dosage form for the P-gp inhibitor.

[0363] It should be apparent to one skilled in the art that the exactdosage and frequency of administration will depend on the particularcompounds of the invention administered, the particular condition beingtreated, the severity of the condition being treated, the age, weight,general physical condition of the particular patient, and othermedication the individual may be taking as is well known toadministering physicians who are skilled in this art.

[0364] Inhibition of APP Cleavage

[0365] The compounds of the invention inhibit cleavage of APP betweenMet595 and Asp596 numbered for the APP695 isoform, or a mutant thereof,or at a corresponding site of a different isoform, such as APP751 orAPP770, or a mutant thereof (sometimes referred to as the “betasecretase site”). While not wishing to be bound by a particular theory,inhibition of beta-secretase activity is thought to inhibit productionof beta amyloid peptide (A beta). Inhibitory activity is demonstrated inone of a variety of inhibition assays, whereby cleavage of an APPsubstrate in the presence of a beta-secretase enzyme is analyzed in thepresence of the inhibitory compound, under conditions normallysufficient to result in cleavage at the beta-secretase cleavage site.Reduction of APP cleavage at the beta-secretase cleavage site comparedwith an untreated or inactive control is correlated with inhibitoryactivity. Assay systems that can be used to demonstrate efficacy of thecompound inhibitors of the invention are known. Representative assaysystems are described, for example, in U.S. Pat. No. 5,942,400,5,744,346, as well as in the Examples below.

[0366] The enzymatic activity of beta-secretase and the production of Abeta can be analyzed in vitro or in vivo, using natural, mutated, and/orsynthetic APP substrates, natural, mutated, and/or synthetic enzyme, andthe test compound. The analysis may involve primary or secondary cellsexpressing native, mutant, and/or synthetic APP and enzyme, animalmodels expressing native APP and enzyme, or may utilize transgenicanimal models expressing the substrate and enzyme. Detection ofenzymatic activity can be by analysis of one or more of the cleavageproducts, for example, by immunoassay, fluorometric or chromogenicassay, HPLC, or other means of detection. Inhibitory compounds aredetermined as those having the ability to decrease the amount ofbeta-secretase cleavage product produced in comparison to a control,where beta-secretase mediated cleavage in the reaction system isobserved and measured in the absence of inhibitory compounds.

[0367] Beta-Secretase

[0368] Various forms of beta-secretase enzyme are known, and areavailable and useful for assay of enzyme activity and inhibition ofenzyme activity. These include native, recombinant, and synthetic formsof the enzyme. Human beta-secretase is known as Beta Site APP CleavingEnzyme (BACE), Asp2, and memapsin 2, and has been characterized, forexample, in U.S. Pat. No. 5,744,346 and published PCT patentapplications WO98/22597, WO0/03819, WO01/23533, and WOOO/17369, as wellas in literature publications (Hussain et al., 1999, Mol. Cell.Neurosci. 14:419-427; Vassar et al., 1999, Science 286:735-741; Yan etal., 1999, Nature 402:533-537; Sinha et al., 1999, Nature 40:537-540;and Lin et al., 2000, PNAS USA 97:1456-1460). Synthetic forms of theenzyme have also been described (WO98/22597 and WO00/17369).Beta-secretase can be extracted and purified from human brain tissue andcan be produced in cells, for example mammalian cells expressingrecombinant enzyme.

[0369] Preferred compounds are effective to inhibit 50% ofbeta-secretase enzymatic activity at a concentration of less than 50micromolar, preferably at a concentration of 10 micromolar or less, morepreferably 1 micromolar or less, and most preferably 10 nanomolar orless.

[0370] APP Substrate

[0371] Assays that demonstrate inhibition of beta-secretase-mediatedcleavage of APP can utilize any of the known forms of APP, including the695 amino acid “normal” isotype described by Kang et al., 1987, Nature325:733-6, the 770 amino acid isotype described by Kitaguchi et. al.,1981, Nature 331:530-532, and variants such as the Swedish Mutation(KM670-1NL) (APP-SW), the London Mutation (V7176F), and others. See, forexample, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature Genet.1:233-234, for a review of known variant mutations. Additional usefulsubstrates include the dibasic amino acid modification, APP-KKdisclosed, for example, in WO 00/17369, fragments of APP, and syntheticpeptides containing the beta-secretase cleavage site, wild type (WT) ormutated form, e.g., SW, as described, for example, in U.S. Pat. No.5,942,400 and WO00/03819.

[0372] The APP substrate contains the beta-secretase cleavage site ofAPP (KM-DA or NL-DA) for example, a complete APP peptide or variant, anAPP fragment, a recombinant or synthetic APP, or a fusion peptide.Preferably, the fusion peptide includes the beta-secretase cleavage sitefused to a peptide having a moiety useful for enzymatic assay, forexample, having isolation and/or detection properties. A useful moietymay be an antigenic epitope for antibody binding, a label or otherdetection moiety, a binding substrate, and the like.

[0373] Antibodies

[0374] Products characteristic of APP cleavage can be measured byimmunoassay using various antibodies, as described, for example, inPirttila et al., 1999, Neuro. Lett. 249:21-4, and in U.S. Pat. No.5,612,486. Useful antibodies to detect A beta include, for example, themonoclonal antibody 6E10 (Senetek, St. Louis, Mo.) that specificallyrecognizes an epitope on amino acids 1-16 of the A beta peptide;antibodies 162 and 164 (New York State Institute for Basic Research,Staten Island, N.Y.) that are specific for human A beta 1-40 and 1-42,respectively; and antibodies that recognize the junction region ofbeta-amyloid peptide, the site between residues 16 and 17, as describedin U.S. Pat. No. 5,593,846. Antibodies raised against a syntheticpeptide of residues 591 to 596 of APP and SW192 antibody raised against590-596 of the Swedish mutation are also useful in immunoassay of APPand its cleavage products, as described in U.S. Pat. Nos. 5,604,102 and5,721,130.

[0375] Assay Systems

[0376] Assays for determining APP cleavage at the beta-secretasecleavage site are well known in the art. Exemplary assays, aredescribed, for example, in U.S. Pat. Nos. 5,744,346 and 5,942,400, anddescribed in the Examples below.

[0377] Cell Free Assays

[0378] Exemplary assays that can be used to demonstrate the inhibitoryactivity of the compounds of the invention are described, for example,in WO00/17369, WO 00/03819, and U.S. Pat. Nos. 5,942,400 and 5,744,346.Such assays can be performed in cell-free incubations or in cellularincubations using cells expressing a beta-secretase and an APP substratehaving a beta-secretase cleavage site.

[0379] An APP substrate containing the beta-secretase cleavage site ofAPP, for example, a complete APP or variant, an APP fragment, or arecombinant or synthetic APP substrate containing the amino acidsequence: KM-DA or NL-DA, is incubated in the presence of beta-secretaseenzyme, a fragment thereof, or a synthetic or recombinant polypeptidevariant having beta-secretase activity and effective to cleave thebeta-secretase cleavage site of APP, under incubation conditionssuitable for the cleavage activity of the enzyme. Suitable substratesoptionally include derivatives that may be fusion proteins or peptidesthat contain the substrate peptide and a modification useful tofacilitate the purification or detection of the peptide or itsbeta-secretase cleavage products. Useful modifications include theinsertion of a known antigenic epitope for antibody binding; the linkingof a label or detectable moiety, the linking of a binding substrate, andthe like.

[0380] Suitable incubation conditions for a cell-free in vitro assayinclude, for example: approximately 200 nanomolar to 10 micromolarsubstrate, approximately 10 to 200 picomolar enzyme, and approximately0.1 nanomolar to 10 micromolar inhibitor compound, in aqueous solution,at an approximate pH of 4-7, at approximately 37 degrees C., for a timeperiod of approximately 10 minutes to 3 hours. These incubationconditions are exemplary only, and can be varied as required for theparticular assay components and/or desired measurement system.Optimization of the incubation conditions for the particular assaycomponents should account for the specific beta-secretase enzyme usedand its pH optimum, any additional enzymes and/or markers that might beused in the assay, and the like. Such optimization is routine and willnot require undue experimentation.

[0381] One useful assay utilizes a fusion peptide having maltose bindingprotein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBPportion is captured on an assay substrate by anti-MBP capture antibody.Incubation of the captured fusion protein in the presence ofbeta-secretase results in cleavage of the substrate at thebeta-secretase cleavage site. Analysis of the cleavage activity can be,for example, by immunoassay of cleavage products. One such immunoassaydetects a unique epitope exposed at the carboxy terminus of the cleavedfusion protein, for example, using the antibody SW192. This assay isdescribed, for example, in U.S. Pat. No. 5,942,400.

[0382] Cellular Assay

[0383] Numerous cell-based assays can be used to analyze beta-secretaseactivity and/or processing of APP to release A beta. Contact of an APPsubstrate with a beta-secretase enzyme within the cell and in thepresence or absence of a compound inhibitor of the invention can be usedto demonstrate beta-secretase inhibitory activity of the compound.Preferably, assay in the presence of a useful inhibitory compoundprovides at least about 30%, most preferably at least about 50%inhibition of the enzymatic activity, as compared with a non-inhibitedcontrol.

[0384] In one embodiment, cells that naturally express beta-secretaseare used. Alternatively, cells are modified to express a recombinantbeta-secretase or synthetic variant enzyme as discussed above. The APPsubstrate may be added to the culture medium and is preferably expressedin the cells. Cells that naturally express APP, variant or mutant formsof APP, or cells transformed to express an isoform of APP, mutant orvariant APP, recombinant or synthetic APP, APP fragment, or syntheticAPP peptide or fusion protein containing the beta-secretase APP cleavagesite can be used, provided that the expressed APP is permitted tocontact the enzyme and enzymatic cleavage activity can be analyzed.

[0385] Human cell lines that normally process A beta from APP provide auseful means to assay inhibitory activities of the compounds of theinvention. Production and release of A beta and/or other cleavageproducts into the culture medium can be measured, for example byimmunoassay, such as Western blot or enzyme-linked immunoassay (EIA)such as by ELISA.

[0386] Cells expressing an APP substrate and an active beta-secretasecan be incubated in the presence of a compound inhibitor to demonstrateinhibition of enzymatic activity as compared with a control. Activity ofbeta-secretase can be measured by analysis of one or more cleavageproducts of the APP substrate. For example, inhibition of beta-secretaseactivity against the substrate APP would be expected to decrease releaseof specific beta-secretase induced APP cleavage products such as A beta.

[0387] Although both neural and non-neural cells process and release Abeta, levels of endogenous beta-secretase activity are low and oftendifficult to detect by EIA. The use of cell types known to have enhancedbeta-secretase activity, enhanced processing of APP to A beta, and/orenhanced production of A beta are therefore preferred. For example,transfection of cells with the Swedish Mutant form of APP (APP-SW); withAPP-KK; or with APP-SW-KK provides cells having enhanced beta-secretaseactivity and producing amounts of A beta that can be readily measured.

[0388] In such assays, for example, the cells expressing APP andbeta-secretase are incubated in a culture medium under conditionssuitable for beta-secretase enzymatic activity at its cleavage site onthe APP substrate. On exposure of the cells to the compound inhibitor,the amount of A beta released into the medium and/or the amount of CTF99fragments of APP in the cell lysates is reduced as compared with thecontrol. The cleavage products of APP can be analyzed, for example, byimmune reactions with specific antibodies, as discussed above.

[0389] Preferred cells for analysis of beta-secretase activity includeprimary human neuronal cells, primary transgenic animal neuronal cellswhere the transgene is APP, and other cells such as those of a stable293 cell line expressing APP, for example, APP-SW.

[0390] In vivo Assays: Animal Models

[0391] Various animal models can be used to analyze beta-secretaseactivity and /or processing of APP to release A beta, as describedabove. For example, transgenic animals expressing APP substrate andbeta-secretase enzyme can be used to demonstrate inhibitory activity ofthe compounds of the invention. Certain transgenic animal models havebeen described, for example, in U.S. Pat. Nos. 5,877,399; 5,612,486;5,387,742; 5,720,936; 5,850,003; 5,877,015,, and 5,811,633, and in Ganeset al., 1995, Nature 373:523. Preferred are animals that exhibitcharacteristics associated with the pathophysiology of AD.Administration of the compound inhibitors of the invention to thetransgenic mice described herein provides an alternative method fordemonstrating the inhibitory activity of the compounds. Administrationof the compounds in a pharmaceutically effective carrier and via anadministrative route that reaches the target tissue in an appropriatetherapeutic amount is also preferred.

[0392] Inhibition of beta-secretase mediated cleavage of APP at thebeta-secretase cleavage site and of A beta release can be analyzed inthese animals by measure of cleavage fragments in the animal's bodyfluids such as cerebral fluid or tissues. Analysis of brain tissues forA beta deposits or plaques is preferred.

[0393] On contacting an APP substrate with a beta-secretase enzyme inthe presence of an inhibitory compound of the invention and underconditions sufficient to permit enzymatic mediated cleavage of APPand/or release of A beta from the substrate, the compounds of theinvention are effective to reduce beta-secretase-mediated cleavage ofAPP at the beta-secretase cleavage site and/or effective to reducereleased amounts of A beta. Where such contacting is the administrationof the inhibitory compounds of the invention to an animal model, forexample, as described above, the compounds are effective to reduce Abeta deposition in brain tissues of the animal, and to reduce the numberand/or size of beta amyloid plaques. Where such administration is to ahuman subject, the compounds are effective to inhibit or slow theprogression of disease characterized by enhanced amounts of A beta, toslow the progression of AD in the, and/or to prevent onset ordevelopment of AD in a patient at risk for the disease.

[0394] Unless defined otherwise, all scientific and technical terms usedherein have the same meaning as commonly understood by one of skill inthe art to which this invention belongs. All patents and publicationsreferred to herein are hereby incorporated by reference for allpurposes.

[0395] Definitions

[0396] The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

[0397] It should be noted that, as used in this specification and theappended claims, the singular forms “a,” “an,” and “the” include pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to a composition containing “a compound” includes amixture of two or more compounds. It should also be noted that the term“or” is generally employed in its sense including “and/or” unless thecontent clearly dictates otherwise.

[0398] The symbol “—” in general represents a bond between two atoms inthe chain. Thus CH₃—O—CH₂—CH(R₁)—CH₃ represents a2-substituted-1-methoxypropane compound. In addition, the symbol “-”represents the point of attachment of the substituent to a compound.Thus for example aryl(C₁-C₆)alkyl- indicates an alkylaryl group, such asbenzyl, attached to the compound at the alkyl moiety.

[0399] Where multiple substituents are indicated as being attached to astructure, it is to be understood that the substituents can be the sameor different. Thus for example “R_(m) optionally substituted with 1, 2or 3 R_(q) groups” indicates that R_(m) is substituted with 1, 2, or 3R_(q) groups where the R_(q) groups can be the same or different.

[0400] APP, amyloid precursor protein, is defined as any APPpolypeptide, including APP variants, mutations, and isoforms, forexample, as disclosed in U.S. Pat. No. 5,766,846.

[0401] A beta, amyloid beta peptide, is defined as any peptide resultingfrom beta-secretase mediated cleavage of APP, including peptides of 39,40, 41, 42, and 43 amino acids, and extending from the beta-secretasecleavage site to amino acids 39, 40, 41, 42, or 43.

[0402] Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl proteasethat mediates cleavage of APP at the amino-terminal edge of A beta.Human beta-secretase is described, for example, in WO00/17369.

[0403] Pharmaceutically acceptable refers to those properties and/orsubstances that are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[0404] A therapeutically effective amount is defined as an amounteffective to reduce or lessen at least one symptom of the disease beingtreated or to reduce or delay onset of one or more clinical markers orsymptoms of the disease.

[0405] By “alkyl” and “C₁-C₆ alkyl” in the present invention is meantstraight or branched chain alkyl groups having 1-6 carbon atoms, suchas, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. It is understood that in cases where an alkyl chain of asubstituent (e.g. of an alkyl, alkoxy or alkenyl group) is shorter orlonger than 6 carbons, it will be so indicated in the second “C” as, forexample, “C₁-C₁₀” indicates a maximum of 10 carbons.

[0406] By “alkoxy” and “C₁-C₆ alkoxy” in the present invention is meantstraight or branched chain alkyl groups having 1-6 carbon atoms,attached through at least one divalent oxygen atom, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and3-methylpentoxy.

[0407] By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

[0408] “Alkenyl” and “C₂-C₆ alkenyl” means straight and branchedhydrocarbon radicals having from 2 to 6 carbon atoms and from one tothree double bonds and includes, for example, ethenyl, propenyl,1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like.

[0409] “Alkynyl” and “C₂-C₆ alkynyl”, means straight and branchedhydrocarbon radicals having from 2 to 6 carbon atoms and one or twotriple bonds and includes ethynyl, propynyl, butynyl, pentyn-2-yl andthe like.

[0410] As used herein, the term “cycloalkyl” refers to saturatedcarbocyclic radicals having three to twelve carbon atoms. The cycloalkylcan be monocyclic, or a polycyclic fused system. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. The cycloalkyl groups herein are unsubstituted or, asspecified, substituted in one or more substitutable positions withvarious groups. For example, such cycloalkyl groups may be optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano,nitro, amino, mono (C₁-C₆) alkylamino, di(C₁-C₆)alkylamino,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

[0411] By “aryl” is meant an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,or trisubstituted. Preferred aryl groups of the present invention arephenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl,tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The arylgroups herein are unsubstituted or, as specified, substituted in one ormore substitutable positions with various groups. For example, such arylgroups may be optionally substituted with, for example, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl,—COOH, —C(═O)O(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)N(mono- or di-C₁-C₆alkyl), —S(C₁-C₆ alkyl), —SO₂(C₁-C₆ alkyl), —O—C(═O)(C₁-C₆ alkyl),—NH—C(═O)—(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-C(═O)—(C₁-C₆ alkyl),—NH—SO₂—(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-SO₂—(C₁-C₆ alkyl), —NH—C(═O)NH₂,—NH—C(═O)N(mono- or di-C₁-C₆ alkyl), —NH(C₁-C₆ alkyl)-C(═O)—NH₂ or—NH(C₁-C₆ alkyl)-C(═O)—N-(mono- or di-C₁-C₆ alkyl).

[0412] By “heteroaryl” is meant one or more aromatic ring systems of 5-,6-, or 7-membered rings which includes fused ring systems of 9-11 atomscontaining at least one and up to four heteroatoms selected fromnitrogen, oxygen, or sulfur. Preferred heteroaryl groups of the presentinvention include pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. The heteroarylgroups herein are unsubstituted or, as specified, substituted in one ormore substitutable positions with various groups. For example, suchheteroaryl groups may be optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, —COOH, —C(═O)O(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)N(mono- or di-C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —SO₂(C₁-C₆ alkyl),—O—C(═O)(C₁-C₆ alkyl), —NH—C(═O)—(C₁-C₆ alkyl), —N(C₁-C₆alkyl)-C(═O)—(C₁-C₆ alkyl), —NH—SO₂—(C₁-C₆ alkyl), —N(C₁-C₆alkyl)-SO₂—(C₁-C₆ alkyl), —NH—C(═O)NH₂, —NH—C(═O)N(mono- or di-C₁-C₆alkyl), —NH(C₁-C₆ alkyl)-C(═O)—NH₂ or —NH(C₁-C₆ alkyl)—C(═O)—N-(mono- ordi-C₁-C₆ alkyl).

[0413] By “heterocycle”, “heterocycloalkyl” or “heterocyclyl” is meantone or more carbocyclic ring systems of 3-, 4-, 5-, 6-, or 7-memberedrings which includes fused ring systems of 9-11 atoms containing atleast one and up to four heteroatoms selected from nitrogen, oxygen, orsulfur. Preferred heterocycles of the present invention includemorpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, azepanyl, diazepanyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide.The heterocycle groups herein maybe unsubstituted or, as specified,substituted in one or more substitutable positions with various groups.For example, such heterocycle groups may be optionally substituted withC₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl or═O.

[0414] All patents and publications referred to herein are herebyincorporated by reference for all purposes.

[0415] Structures were named using Name Pro IUPAC Naming Software,version 5.09, available from Advanced Chemical Development, Inc., 90Adelaide Street West, Toronto, Ontario, M5H 3V9, Canada.

[0416] The present invention may be better understood with reference tothe following examples. These examples are intended to be representativeof specific embodiments of the invention, and are not intended aslimiting the scope of the invention.

CHEMISTRY EXAMPLES

[0417] The following abbreviations may be used in the Examples:

[0418] EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or thehydrochloride salt);

[0419] DIEA (diisopropylethylamine);

[0420] PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate);

[0421] HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate);

[0422] DCM (dichloromethane).

Example 1 Synthesis of (4(R)-Amino-1(S)-benzyl-2(R),3(R)-dihydroxy-pentyl)-carbamic acid tert-butyl ester

[0423]

[0424] In a flame dried, three-necked flask, a mixture of VCl₃(THF)₃(31.50 mmol) and zinc dust (19.68 mmol) in anhydrous CH₂Cl₂ (150 mL) isstirred vigorously for 0.5 h to give a green solution. To this mixture,a solution of (1(S)-methyl-2-oxo-ethyl)-carbamic acid benzyl ester (1.73mmol) and (1(S)-formyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester(1.73 mmol) in anhydrous CH₂Cl₂ (30 mL) is added slowly over 60 min. Thesolution is stirred for an additional 45 min, poured into 10% aqueoussodium tartrate (400 mL) and stirred vigorously overnight. The layersare separated and the aqueous phase is extracted with CH₂Cl₂. Thecombined organic layers are washed with saturated NaHCO₃, dried (MgSO₄),filtered and concentrated under reduced pressure. The residue ispurified via flash chromatography on silica gel using 1:1:2 to 1:1:1Et₂O/CH₂Cl₂/hexanes to give the diol.

[0425] A slurry of the diol (2 mmol) and 10% Pd/C (5 mole %) is stirredunder 1 atm of hydrogen gas for 4 h. The reaction mixture is filteredthrough Celite to give (4(R) -amino-1(S)-benzyl-2(R),3(R)-dihydroxy-pentyl)-carbamic acid tert-butyl ester.

Example 2 Synthesis of Compound 2

[0426] A mixture of the benzoic acid (1.0 eq), HATU (1.2 eq.) and DIEA(2.4 eq.) in DMF (2 mL) is rocked at rt for 1 h. A solution of(4(R)-amino-1(S)-benzyl-2(R),3(R)-dihydroxy-pentyl)-carbamic acidtert-butyl ester (2.0 eq) in DCM (1 mL) is added, and the reactionmixture rocked at rt overnight. The reaction is concentrated,redissolved in MeOH (2 mL for 3 mL) and Dowex 50WX2-400 (10 eq.) andMP-carbonate (10 eq.) added. The mixture is rocked for 2 h at rt,filtered and the resins washed with MeOH. The filtrate and washes arecombined and concentrated. A 1000 mg C18 SPE cartridge is conditionedwith 3 mL/6 mL MeCN, then 3 mL/6 mL 5%MeCN/0.1% TFA:water. The reactionresidue is loaded onto the cartridge using (2×100 uL) DMF and elutedwith 6 mL each of 5%, 10%, 15%, 25%, 50%, 100% MeCN/0.1% TFA:water. Thefractions are analyzed by HPLC and the appropriate fractions arecombined to give the desired adduct.

[0427] The adduct is dissolved in dioxane (2 mL), cooled to 0° C. and a2M solution of HCl in dioxane is added via syringe. The mixture isallowed to warm to rt and stir for 2 h. The reaction mixture isconcentrated in vacuo and redisolved in DMF (3 mL),2-methane-sulfonylamino-thiazole- 4-carboxylic acid (1.0 eq) is thenadded followed by HATU (1.2 eq.) and DIEA (2.4 eq.). The reactionmixture is rocked at rt overnight. The mixture is concentrated,redissolved in MeOH (2 mL for 3 mL) and Dowex 50WX2-400 (10 eq.) andMP-carbonate (10 eq.) added. The mixture is rocked for 2 h at rt,filtered and the resins washed with MeOH. The filtrate and washes arecombined and concentrated. A 1000 mg C18 SPE cartridge is conditionedwith 3 mL/6 mL MeCN, then 3 mL/6 mL 5%MeCN/0.1% TFA:water. The reactionresidue is loaded onto the cartridge using (2×100 uL) DMF and elutedwith 6 mL each of 5%, 10%, 15%, 25%, 50%, 100% MeCN/0.1% TFA:water. Thefractions are analyzed by HPLC and the appropriate fractions arecombined to give compound 2.

Example 3 Synthesis of Compound 21

[0428] A mixture of the acetic acid (1.0 eq), HATU (1.2 eq.) and DIEA(2.4 eq.) in DMF (2 mL) is rocked at rt for 1 h. A solution of(4(R)-amino-1(S)-benzyl-2(R),3(R)-dihydroxy-pentyl)-carbamic acidtert-butyl ester (2.0 eq) in DCM (1 mL) is added, and the reactionmixture rocked at rt overnight. The reaction is concentrated,redissolved in MeOH (2 mL for 3 mL) and Dowex 50WX2-400 (10 eq.) andMP-carbonate (10 eq.) added. The mixture is rocked for 2 h at rt,filtered and the resins washed with MeOH. The filtrate and washes arecombined and concentrated. A 1000 mg C18 SPE cartridge is conditionedwith 3 mL/6 mL MeCN, then 3 mL/6 mL 5%MeCN/0.1% TFA:water. The reactionresidue is loaded onto the cartridge using (2×100 uL) DMF and elutedwith 6 mL each of 5%, 10%, 15%, 25%, 50%, 100% MeCN/0.1% TFA:water. Thefractions are analyzed by HPLC and the appropriate fractions arecombined to give the desired adduct.

[0429] The adduct is dissolved in dioxane (2 mL), cooled to 0° C. and a2M solution of HCl in dioxane is added via syringe. The mixture isallowed to warm to rt and stir for 2 h. The reaction mixture isconcentrated in vacuo and redisolved in DMF (3 mL),N-methyl-2-methane-sulfonylamino-oxazole-4-carboxylic acid (1.0 eq) isthen added followed by HATU (1.2 eq.) and DIEA (2.4 eq.). The reactionmixture is rocked at rt overnight. The mixture is concentrated,redissolved in MeOH (2 mL for 3 mL) and Dowex 50WX2-400 (10 eq.) andMP-carbonate (10 eq.) added. The mixture is rocked for 2 h at rt,filtered and the resins washed with MeOH. The filtrate and washes arecombined and concentrated. A 1000 mg C18 SPE cartridge is conditionedwith 3 mL/6 mL MeCN, then 3 mL/6 mL 5%MeCN/0.1% TFA:water. The reactionresidue is loaded onto the cartridge using (2×100 uL) DMF and elutedwith 6 mL each of 5%, 10%, 15%, 25%, 50%, 100% MeCN/0.1% TFA:water. Thefractions are analyzed by HPLC and the appropriate fractions arecombined to give compound 21.

Example 4 Synthesis of Compound 23

[0430] A mixture of the benzoic acid (1.0 eq), HATU (1.2 eq.) and DIEA(2.4 eq.) in DMF (2 mL) is rocked at rt for 1 h. A solution of(4(R)-amino-1(S)-benzyl-2(R),3(R)-dihydroxy-pentyl)-carbamic acidtert-butyl ester (2.0 eq) in DCM (1 mL) is added, and the reactionmixture rocked at rt overnight. The reaction is concentrated,redissolved in MeOH (2 mL for 3 mL) and Dowex 50WX2-400 (10 eq.) andMP-carbonate (10 eq.) added. The mixture is rocked for 2 h at rt,filtered and the resins washed resins with MeOH. The filtrate and washesare combined and concentrated. A 1000 mg C18 SPE cartridge isconditioned with 3 mL/6 mL MeCN, then 3 mL/6 mL 5%MeCN/0.1% TFA:water.The reaction residue is loaded onto the cartridge using (2×100 uL) DMFand eluted with 6 mL each of 5%, 10%, 15%, 25%, 50%, 100% MeCN/0.1%TFA:water. The fractions are analyzed by HPLC and the appropriatefractions are combined to give the desired adduct.

[0431] The adduct is dissolved in dioxane (2 mL), cooled to 0° C. and a2M solution of HCl in dioxane is added via syringe. The mixture isallowed to warm to rt and stir for 2 h. The reaction mixture isconcentrated in vacuo and redisolved in DMF (3 mL),N-methyl-2-methane-sulfonylamino-oxazole -4-carboxylic acid (1.0 eq) isthen added followed by HATU (1.2 eq.) and DIEA (2.4 eq.). The reactionmixture is rocked at rt overnight. The mixture is concentrated,redissolved in MeOH (2 mL for 3 mL) and Dowex 50WX2-400 (10 eq.) andMP-carbonate (10 eq.) added. The mixture is rocked for 2 h at rt,filtered and the resins washed with MeOH. The filtrate and washes arecombined and concentrated. A 1000 mg C18 SPE cartridge is conditionedwith 3 mL/6 mL MeCN, then 3 mL/6 mL 5%MeCN/0.1% TFA:water. The reactionresidue is loaded onto the cartridge using (2×100 uL) DMF and elutedwith 6 mL each of 5%, 10%, 15%, 25%, 50%, 100% MeCN/0.1% TFA:water. Thefractions are analyzed by HPLC and the appropriate fractions arecombined to give compound 23.

Example 5 Synthesis of Compound 42

[0432] A mixture of the benzoic acid (1.0 eq), HATU (1.2 eq.) and DIEA(2.4 eq.) in DMF (2 mL) is rocked at rt for 1 h. A solution of(4(R)-amino-1(S)-benzyl-2(R),3(R)-dihydroxy-pentyl)-carbamic acidtert-butyl ester (2.0 eq) in DCM (1 mL) is added, and the reactionmixture rocked at rt overnight. The reaction is concentrated,redissolved in MeOH (2 mL for 3 mL) and Dowex 50WX2-400 (10 eq.) andMP-carbonate (10 eq.) added. The mixture is rocked for 2 h at rt,filtered and the resins washed resins with MeOH. The filtrate and washesare combined and concentrated. A 1000 mg C18 SPE cartridge isconditioned with 3 mL/6 mL MeCN, then 3 mL/6 mL 5%MeCN/0.1% TFA:water.The reaction residue is loaded onto the cartridge using (2×100 uL) DMFand eluted with 6 mL each of 5%, 10%, 15%, 25%, 50%, 100% MeCN/0.1%TFA:water. The fractions are analyzed by HPLC and the appropriatefractions are combined to give the desired adduct.

[0433] The adduct is dissolved in dioxane (2 mL), cooled to 0° C. and a2M solution of HCl in dioxane is added via syringe. The mixture isallowed to warm to rt and stir for 2 h. The reaction mixture isconcentrated in vacuo and redisolved in DMF (3 mL),3-methyl-5-[(dipropylamino)carbonyl]benzoic acid (1.0 eq) is then addedfollowed by HATU (1.2 eq.) and DIEA (2.4 eq.). The reaction mixture isrocked at rt overnight. The mixture is concentrated, redissolved in MeOH(2 mL for 3 mL) and Dowex 50WX2-400 (10 eq.) and MP-carbonate (10 eq.)added. The mixture is rocked for 2 h at rt, filtered and the resinswashed with MeOH. The filtrate and washes are combined and concentrated.A 1000 mg C18 SPE cartridge is conditioned with 3 mL/6 mL MeCN, then 3mL/6 mL 5%MeCN/0.1% TFA:water. The reaction residue is loaded onto thecartridge using (2×100 uL) DMF and eluted with 6 mL each of 5%, 10%,15%, 25%, 50%, 100% MeCN/0.1% TFA:water. The fractions are analyzed byHPLC and the appropriate fractions are combined to give compound 42.

[0434] The following compounds are prepared essentially according to theprocedures described in the schemes, charts, examples and preparationsset forth herein. Number Compound

[0435]5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0436]5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0437]N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

[0438]N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

[0439]5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,

[0440]5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,

[0441]5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,

[0442]5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,

[0443]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0444]5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0445]5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0446]5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0447]N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

[0448]N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

[0449] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,

[0450] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,

[0451] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,

[0452] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,

[0453]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0454] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0455]5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0456]5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0457] N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

[0458] N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

[0459] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,

[0460] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,

[0461] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,

[0462] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,

[0463]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0464] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0465]5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0466]5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0467] N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

[0468] N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

[0469] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,

[0470] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,

[0471] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,

[0472] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,

[0473]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0474] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,

[0475]5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol,

[0476]5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol,

[0477] N′-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,

[0478] N′-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,

[0479]5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol,

[0480]5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol,

[0481]5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-1-phenyl-D-gluco-heptitol,

[0482]5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-1-phenyl-D-gluco-heptitol,

[0483]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol,

[0484] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol,

[0485] 5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl] benzoyl}amino) -1,2,5,6-tetradeoxy-1-phenyl-D-glucitol,

[0486] 2-({3-(aminocarbonyl)-5-[(dipropylamino) carbonyl] benzoyl}amino)-5-(benzoylamino) -1,2,5, 6-tetradeoxy-1-phenyl-D-glucitol,

[0487] N³-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

[0488] N³-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

[0489]5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol,

[0490]2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol,

[0491]5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-D-gluco-heptitol,

[0492]2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-D-gluco-heptitol,

[0493]5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol,

[0494]2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol,

[0495]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol,

[0496]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol,

[0497]N′-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,

[0498]N′-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,

[0499]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-7-thio-D-gluco-heptitol,

[0500]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-7-thio-D-gluco-heptitol,

[0501]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-D-gluco-heptitol,

[0502]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-D-gluco-heptitol,

[0503]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol,

[0504] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol,

[0505]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,

[0506]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,

[0507]N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

[0508] N-[(1S,2R,3R4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

[0509]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,

[0510]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,

[0511]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol,

[0512]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol,

[0513]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,

[0514] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,

[0515]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,

[0516]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,

[0517]N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

[0518]N-[(1S,2R,3R,4R)-4-(benzoylamino)-1(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

[0519]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,

[0520]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,

[0521]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol,

[0522]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol,

[0523]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,

[0524] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,

[0525]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,

[0526]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,

[0527]N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

[0528]N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]1-1,3-oxazole-4-carboxamide,

[0529]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,

[0530]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,

[0531]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol,

[0532]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol,

[0533]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,

[0534] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,

[0535]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,

[0536]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,

[0537] N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

[0538]N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

[0539]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,

[0540]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,

[0541]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol,

[0542]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol,

[0543]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,

[0544] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,

[0545]5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol,

[0546]2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol,

[0547]N³-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

[0548]N³-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

[0549]5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-7-thio-D-gluco-heptitol,

[0550]2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-7-thio-D-gluco-heptitol,

[0551]5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-D-gluco-heptitol,

[0552]2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-D-gluco-heptitol,

[0553]5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol,

[0554]2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol,

[0555] 5-(acetylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0556] 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0557]N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

[0558] N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

[0559] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,

[0560] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,

[0561] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,

[0562] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,

[0563]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0564] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0565] 5-(acetylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0566] 5-(benzoylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0567]N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide,

[0568] N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide,

[0569] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,

[0570] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,

[0571] 5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,

[0572] 5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,

[0573]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol

[0574] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0575]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0576]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0577]N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

[0578] N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

[0579]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,

[0580]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,

[0581]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,

[0582]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,

[0583]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino) -D-glucitol,

[0584] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0585]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2?)-2-[(pyridin-3-ylcarbonyl)amino] octanoyl}amino)-D-glucitol,

[0586]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0587]N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide,

[0588] N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide,

[0589]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,

[0590]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,

[0591]5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,

[0592]5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,

[0593]5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

[0594] 5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,

BIOLOGY EXAMPLES Example A

[0595] Enzyme Inhibition Assay

[0596] The compounds of the invention are analyzed for inhibitoryactivity by use of the MBP-C125 assay. This assay determines therelative inhibition of beta-secretase cleavage of a model APP substrate,MBP-C125SW, by the compounds assayed as compared with an untreatedcontrol. A detailed description of the assay parameters can be found,for example, in U.S. Pat. No. 5,942,400. Briefly, the substrate is afusion peptide formed of maltose binding protein (MBP) and the carboxyterminal 125 amino acids of APP-SW, the Swedish mutation. Thebeta-secretase enzyme is derived from human brain tissue as described inSinha et al, 1999, Nature 40:537-540) or recombinantly produced as thefull-length enzyme (amino acids 1-501), and can be prepared, forexample, from 293 cells expressing the recombinant cDNA, as described inWO00/47618.

[0597] Inhibition of the enzyme is analyzed, for example, by immunoassayof the enzyme's cleavage products. One exemplary ELISA uses an anti-MBPcapture antibody that is deposited on precoated and blocked 96-well highbinding plates, followed by incubation with diluted enzyme reactionsupernatant, incubation with a specific reporter antibody, for example,biotinylated anti-SW192 reporter antibody, and further incubation withstreptavidin/alkaline phosphatase. In the assay, cleavage of the intactMBP-C125SW fusion protein results in the generation of a truncatedamino-terminal fragment, exposing a new SW-192 antibody-positive epitopeat the carboxy terminus. Detection is effected by a fluorescentsubstrate signal on cleavage by the phosphatase. ELISA only detectscleavage following Leu 596 at the substrate's APP-SW 751 mutation site.

[0598] Specific Assay Procedure:

[0599] Compounds are diluted in a 1:1 dilution series to a six-pointconcentration curve (two wells per concentration) in one 96-plate rowper compound tested. Each of the test compounds is prepared in DMSO tomake up a 10 millimolar stock solution. The stock solution is seriallydiluted in DMSO to obtain a final compound concentration of 200micromolar at the high point of a 6-point dilution curve. Ten (10)microliters of each dilution is added to each of two wells on row C of acorresponding V-bottom plate to which 190 microliters of 52 millimolarNaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc diluted compound plateis spun down to pellet precipitant and 20 microliters/well istransferred to a corresponding flat-bottom plate to which 30 microlitersof ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SWsubstrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09%TX100 per 30 microliters) is added. The final reaction mixture of 200micromolar compound at the highest curve point is in 5% DMSO, 20millimolar NaOAc, 0.06% TX100, at pH 4.5.

[0600] Warming the plates to 37 degrees C. starts the enzyme reaction.After 90 minutes at 37 degrees C., 200 microliters/well cold specimendiluent is added to stop the reaction and 20 microliters/well wastransferred to a corresponding anti-MBP antibody coated ELISA plate forcapture, containing 80 microliters/well specimen diluent. This reactionis incubated overnight at 4 degrees C. and the ELISA is developed thenext day after a 2 hour incubation with anti-192SW antibody, followed byStreptavidin-AP conjugate and fluorescent substrate. The signal is readon a fluorescent plate reader.

[0601] Relative compound inhibition potency is determined by calculatingthe concentration of compound that showed a fifty percent reduction indetected signal (IC₅₀) compared to the enzyme reaction signal in thecontrol wells with no added compound. In this assay, preferred compoundsof the invention exhibit an IC₅₀ of less than 50 micromolar.

Example B

[0602] Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

[0603] A synthetic APP substrate that can be cleaved by beta-secretaseand having N-terminal biotin and made fluorescent by the covalentattachment of Oregon green at the Cys residue is used to assaybeta-secretase activity in the presence or absence of the inhibitorycompounds of the invention. Useful substrates include the following:Biotin-SEVNL-DAEFRC[oregon green]KK [SEQ ID NO:1]Biotin-SEVKM-DAEFRC[oreqon green]KK [SEQ ID NO:2]Biotin-GLNIKTEEISETSY-EVEFRC[oregon [SEQ ID NO:3] green]KKBiotin-ADRGLTTRPGSGLTNIKTEEISEVNL- [SEQ ID NO:4] DAEFRC[oregon green]KKBiotin-FVNQHLCoxGSHLVEALY- [SEQ ID NO:5] LVCoxGERGFFYTPKAC[oregongreen]KK

[0604] The enzyme (0.1 nanomolar) and test compounds (0.001-100micromolar) are incubated in pre-blocked, low affinity, black plates(384 well) at 37 degrees for 30 minutes. The reaction is initiated byaddition of 150 millimolar substrate to a final volume of 30 microliterper well. The final assay conditions are: 0.001-100 micromolar compoundinhibitor; 0.1 molar sodium acetate (pH 4.5); 150 nanomolar substrate;0.1 nanomolar soluble beta-secretase; 0.001% Tween 20, and 2% DMSO. Theassay mixture is incubated for 3 hours at 37 degrees C., and thereaction is terminated by the addition of a saturating concentration ofimmunopure streptavidin. After incubation with streptavidin at roomtemperature for 15 minutes, fluorescence polarization is measured, forexample, using a LJL Acqurest (Ex485 nm/Em530 nm). The activity of thebeta-secretase enzyme is detected by changes in the fluorescencepolarization that occur when the substrate is cleaved by the enzyme.Incubation in the presence or absence of compound inhibitor demonstratesspecific inhibition of beta-secretase enzymatic cleavage of itssynthetic APP substrate. In this assay, preferred compounds of theinvention exhibit an IC₅₀ of less than 50 micromolar.

Example C

[0605] Beta-Secretase Inhibition: P26-P4′SW Assay

[0606] Synthetic substrates containing the beta-secretase cleavage siteof APP are used to assay beta-secretase activity, using the methodsdescribed, for example, in published PCT application WO00/47618. TheP26-P4′SW substrate is a peptide of the sequence: (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVN [SEQ ID NO:6] LDAEF The P26-P1 standard hasthe sequence: (biotin) CGGADRGLTTRPGSGLTNIKTEEISEVN [SEQ ID NO:7] L

[0607] Briefly, the biotin-coupled synthetic substrates are incubated ata concentration of from about 0 to about 200 micromolar in this assay.When testing inhibitory compounds, a substrate concentration of about1.0 micromolar is preferred. Test compounds diluted in DMSO are added tothe reaction mixture, with a final DMSO concentration of 5%. Controlsalso contain a final DMSO concentration of 5%. The concentration of betasecretase enzyme in the reaction is varied, to give productconcentrations with the linear range of the ELISA assay, about 125 to2000 picomolar, after dilution.

[0608] The reaction mixture also includes 20 millimolar sodium acetate,pH 4.5, 0.06% Triton X100, and is incubated at 37 degrees C. for about 1to 3 hours. Samples are then diluted in assay buffer (for example, 145.4nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7millimolar sodium azide, 0.05% Triton X405, 6 g/liter bovine serumalbumin, pH 7.4) to quench the reaction, then diluted further forimmunoassay of the cleavage products.

[0609] Cleavage products can be assayed by ELISA. Diluted samples andstandards are incubated in assay plates coated with capture antibody,for example, SW192, for about 24 hours at 4 degrees C. After washing inTTBS buffer (150 millimolar sodium chloride, 25 millimolar Tris, 0.05%Tween 20, pH 7.5), the samples are incubated with streptavidin-APaccording to the manufacturer's instructions. After a one hourincubation at room temperature, the samples are washed in TTBS andincubated with fluorescent substrate solution A (31.2 g/liter2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction withstreptavidin-alkaline phosphate permits detection by fluorescence.Compounds that are effective inhibitors of beta-secretase activitydemonstrate reduced cleavage of the substrate as compared to a control.

Example D

[0610] Assays using Synthetic Oligopeptide-Substrates

[0611] Synthetic oligopeptides are prepared that incorporate the knowncleavage site of beta-secretase, and optionally detectable tags, such asfluorescent or chromogenic moieties. Examples of such peptides, as wellas their production and detection methods are described in U.S. Pat. No.5,942,400, herein incorporated by reference. Cleavage products can bedetected using high performance liquid chromatography, or fluorescent orchromogenic detection methods appropriate to the peptide to be detected,according to methods well known in the art.

[0612] By way of example, one such peptide has the sequence SEVNL-DAEF[SEQ ID NO: 8], and the cleavage site is between residues 5 and 6.Another preferred substrate has the sequenceADRGLTTRPGSGLTNIKTEEISEVNL-DAEF [SEQ ID NO: 9], and the cleavage site isbetween residues 26 and 27.

[0613] These synthetic APP substrates are incubated in the presence ofbeta-secretase under conditions sufficient to result in beta-secretasemediated cleavage of the substrate. Comparison of the cleavage resultsin the presence of the compound inhibitor to control results provides ameasure of the compound's inhibitory activity.

Example E

[0614] Inhibition of Beta-Secretase Activity—Cellular Assay

[0615] An exemplary assay for the analysis of inhibition ofbeta-secretase activity utilizes the human embryonic kidney cell lineHEKp293 (ATCC Accession No. CRL-1573) transfected with APP751 containingthe naturally occurring double mutation Lys651Met52 to Asn651Leu652(numbered for APP751), commonly called the Swedish mutation and shown tooverproduce A beta (Citron et al., 1992, Nature 360:672-674), asdescribed in U.S. Pat. No. 5,604,102.

[0616] The cells are incubated in the presence/absence of the inhibitorycompound (diluted in DMSO) at the desired concentration, generally up to10 micrograms/ml. At the end of the treatment period, conditioned mediais analyzed for beta-secretase activity, for example, by analysis ofcleavage fragments. A beta can be analyzed by immunoassay, usingspecific detection antibodies. The enzymatic activity is measured in thepresence and absence of the compound inhibitors to demonstrate specificinhibition of beta-secretase mediated cleavage of APP substrate.

Example F

[0617] Inhibition of Beta-Secretase in Animal Models of AD

[0618] Various animal models can be used to screen for inhibition ofbeta-secretase activity. Examples of animal models useful in theinvention include, but are not limited to, mouse, guinea pig, dog, andthe like. The animals used can be wild type, transgenic, or knockoutmodels. In addition, mammalian models can express mutations in APP, suchas APP695-SW and the like described herein. Examples of transgenicnon-human mammalian models are described in U.S. Pat. Nos. 5,604,102,5,912,410 and 5,811,633.

[0619] PDAPP mice, prepared as described in Games et al., 1995, Nature373:523-527 are useful to analyze in vivo suppression of A beta releasein the presence of putative inhibitory compounds. As described in U.S.Pat. No. 6,191,166, 4 month old PDAPP mice are administered compoundformulated in vehicle, such as corn oil. The mice are dosed withcompound (1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10hours, the animals are sacrificed, and brains removed for analysis.

[0620] Transgenic animals are administered an amount of the compoundinhibitor formulated in a carrier suitable for the chosen mode ofadministration. Control animals are untreated, treated with vehicle, ortreated with an inactive compound. Administration can be acute, i.e.,single dose or multiple doses in one day, or can be chronic, i.e.,dosing is repeated daily for a period of days. Beginning at time 0,brain tissue or cerebral fluid is obtained from selected animals andanalyzed for the presence of APP cleavage peptides, including A beta,for example, by immunoassay using specific antibodies for A betadetection. At the end of the test period, animals are sacrificed andbrain tissue or cerebral fluid is analyzed for the presence of A betaand/or beta-amyloid plaques. The tissue is also analyzed for necrosis.

[0621] Animals administered the compound inhibitors of the invention areexpected to demonstrate reduced A beta in brain tissues or cerebralfluids and reduced beta amyloid plaques in brain tissue, as comparedwith non-treated controls.

Example G

[0622] Inhibition of A Beta Production in Human Patients

[0623] Patients suffering from Alzheimer's Disease (AD) demonstrate anincreased amount of A beta in the brain. AD patients are administered anamount of the compound inhibitor formulated in a carrier suitable forthe chosen mode of administration. Administration is repeated daily forthe duration of the test period. Beginning on day 0, cognitive andmemory tests are performed, for example, once per month.

[0624] Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; A beta depositsin the brain; amyloid plaque in the brain; and scores for cognitive andmemory function, as compared with control, non-treated patients.

Example H

[0625] Prevention of A Beta Production in Patients at Risk for AD

[0626] Patients predisposed or at risk for developing AD are identifiedeither by recognition of a familial inheritance pattern, for example,presence of the Swedish Mutation, and/or by monitoring diagnosticparameters. Patients identified as predisposed or at risk for developingAD are administered an amount of the compound inhibitor formulated in acarrier suitable for the chosen mode of administration. Administrationis repeated daily for the duration of the test period. Beginning on day0, cognitive and memory tests are performed, for example, once permonth.

[0627] Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; amyloid plaque inthe brain; and scores for cognitive and memory function, as comparedwith control, non-treated patients.

[0628] The invention has been described with reference to variousspecific and preferred embodiments and techniques. However, it should beunderstood that many variations and modifications may be made whileremaining within the spirit and scope of the invention.

1 9 1 13 PRT Artificial Sequence synthetic peptide 1 Ser Glu Val Asn LeuAsp Ala Glu Phe Arg Cys Lys Lys 1 5 10 2 13 PRT Artificial Sequencesynthetic peptide 2 Ser Glu Val Lys Met Asp Ala Glu Phe Arg Cys Lys Lys1 5 10 3 22 PRT Artificial Sequence synthetic peptide 3 Gly Leu Asn IleLys Thr Glu Glu Ile Ser Glu Ile Ser Tyr Glu Val 1 5 10 15 Glu Phe ArgCys Lys Lys 20 4 34 PRT Artificial Sequence synthetic peptide 4 Ala AspArg Gly Leu Thr Thr Arg Pro Gly Ser Gly Leu Thr Asn Ile 1 5 10 15 LysThr Glu Glu Ile Ser Glu Val Asn Leu Asp Ala Glu Phe Arg Cys 20 25 30 LysLys 5 33 PRT Artificial Sequence synthetic peptide 5 Phe Val Asn Gln HisLeu Cys Gly Ser His Leu Val Glu Ala Leu Tyr 1 5 10 15 Leu Val Cys GlyGlu Arg Gly Phe Phe Tyr Thr Pro Lys Ala Cys Lys 20 25 30 Lys 6 33 PRTArtificial Sequence synthetic peptide 6 Cys Gly Gly Ala Asp Arg Gly LeuThr Thr Arg Pro Gly Ser Gly Leu 1 5 10 15 Thr Asn Ile Lys Thr Glu GluIle Ser Glu Val Asn Leu Asp Ala Glu 20 25 30 Phe 7 29 PRT ArtificialSequence synthetic peptide 7 Cys Gly Gly Ala Asp Arg Gly Leu Thr Thr ArgPro Gly Ser Gly Leu 1 5 10 15 Thr Asn Ile Lys Thr Glu Glu Ile Ser GluVal Asn Leu 20 25 8 9 PRT Artificial Sequence synthetic peptide 8 SerGlu Val Asn Leu Asp Ala Glu Phe 1 5 9 30 PRT Artificial Sequencesynthetic peptide 9 Ala Asp Arg Gly Leu Thr Thr Arg Pro Gly Ser Gly LeuThr Asn Ile 1 5 10 15 Lys Thr Glu Glu Ile Ser Glu Val Asn Leu Asp AlaGlu Phe 20 25 30

What is claimed is:
 1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof, wherein R₁ is C₁-C₁₀alkyl optionally substituted with 1, 2, or 3 groups independentlyselected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy,—S—(C₁-C₃)alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or C₂-C₆ alkenyl orC₂-C₆ alkynyl, each of which is optionally substituted with 1, 2, or 3groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, amino, and mono- or dialkylamino, or aryl, heteroaryl,heterocyclyl, aryl (C₁-C₆) alkyl-, heteroaryl(C₁-C₆)alkyl-, orheterocyclyl(C₁-C₆)alkyl-, where the ring portions of each areoptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′,—N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-monoalkylamino,—SO₂-dialkylamino, —C(═O)-amino, —C(═O)-monoalkylamino,—C(═O)-dialkylamino, —SO₂—(C₁-C₄) alkyl, C₁-C₆ alkoxy optionallysubstituted with 1, 2, or 3 groups which are independently selected fromhalogen, C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, —C₁-C₆ alkyl and mono- or dialkylamino, C₁-C₁₀ alkyl optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and—C₁-C₃ alkyl, and C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which isoptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl andmono- or dialkylamino; and the heterocyclyl group is optionally furthersubstituted with oxo; R and R′ independently are hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ alkylaryl or C₁-C₁₀ alkylheteroaryl; R₁′ is phenyl-(C₁-C₆)alkyl-where the phenyl ring is optionally substituted with 1, 2, 3, or 4groups independently selected from halogen, —OH, —SH, —C≡N, —NO₂,—NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl,—SO₂-amino, —SO₂-monoalkylamino, —SO₂-dialkylamino, —C (═O)-amino,—C(═O)-monoalkylamino, —C(═O)-dialkylamino, —SO₂—(C₁-C₄) alkyl, C₁-C₆alkoxy optionally substituted with 1, 2, or 3 groups which areindependently selected from halogen, C₃-C₇ cycloalkyl optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- ordialkylamino, C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, and C₂-C₁₀alkenyl or C₂-C₁₀ alkynyl each of which is optionally substituted with1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino; andthe heterocyclyl group is optionally further substituted with oxo,  withthe proviso that R₁ and R₁′ are not simultaneously unsubstitutedphenyl-(CH₂)—, R₂₀ at each occurrence is independently H or C₁-C₆ alkyl;R_(N) and R_(N)′ are independently R′₁₀₀, —SO₂R′₁₀₀, —(CRR′)₁₋₆R′₁₀₀,—C(═O)—(CRR′)₀₋₆R₁₀₀, —C(═O—)—(CRR′)₁₋₆—O—R′₁₀₀,—C(═O)—(CRR′)₁₋₆—S—R′₁₀₀, or —C(═O)—(CRR′)₁₋₆—NR₁₀₀—R′₁₀₀; R₁₀₀ andR′₁₀₀ independently represent aryl, heteroaryl, heterocyclyl,-aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl,-heteroaryl-W-aryl, -heteroaryl-W-heteroaryl,-heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl,-heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl,—CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-aryl, or —CH[(CH₂)₀₋₂—O—R₁₅₀]—(CH₂)₀₋₂-heteroaryl, where the ring portions of eachare optionally substituted with 1, 2, or 3 groups independently selectedfrom —OR, —NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃,—(CH₂)₀₋₄—O—P(═O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,—(CH₂)₀₋₄—O—CO—N(R₁₅O)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),—(CH₂)₀₋₄—O—R₁₅₀—COOH, —(CH₂)₀₄—S—(R₁₅₀),—(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R_(150, —(CH) ₂)₀₋₄—C₃-C₇ cycloalkyl,(C₂-C₁₀)alkenyl, and (C₂-C₁₀)alkynyl, or R₁₀₀ is C₁-C₁₀ alkyl optionallysubstituted with 1, 2, or 3 R₁₁₅ groups, or R₁₀₀ is —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl) or —(C₁-C₆ alkyl)-S—(C₁-C₆ alkyl), each of whichis optionally substituted with 1, 2, or 3 R₁₁₅ groups, or R₁₀₀ is C₃-C₈cycloalkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups; W is—(CH₂)₀₋₄—, —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, —CR(OH)— or —C(O)—; R₁₀₂ andR₁₀₂′ independently are hydrogen, or C₁-C₁₀ alkyl optionally substitutedwith 1, 2, or 3 groups that are independently halogen, aryl or —R₁₁₀;R₁₀₅ and R′₁₀₅ independently represent —H, —R₁₁₀, —R₁₂₀, C₃-C₇cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃alkyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ alkyl chain with onedouble bond and one triple bond, or C₁-C₆ alkyl optionally substitutedwith —OH or —NH₂; or, C₁-C₆ alkyl optionally substituted with 1, 2, or 3groups independently selected from halogen, or R₁₀₅ and R′₁₀₅ togetherwith the atom to which they are attached form a 3 to 7 memberedcarbocylic ring, where one member is optionally a heteratom selectedfrom —O—, —S(O)₀₋₂—, —N(R₁₃₅)—, the ring being optionally substitutedwith 1, 2 or 3 independently selected R₁₄₀ groups; R₁₁₅ at eachoccurrence is independently halogen, —OH, —CO₂R₁₀₂, —C₁-C₆ thioalkoxy,—CO₂-phenyl, —NR₁₀₅R′₁₀₅, —SO₂—(C₁-C₈ alkyl), —C(═O)R₁₈₀, R₁₈₀,—CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅, —NH—CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀,—NH—CO—R₁₂₀, —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O—phenyl,—O—C(═O)—(C₁-C₆ alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino,—O—C(═O)-phenyl, —O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆alkoxy or C₁-C₆ haloalkoxy; R₁₃₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₇ cycloalkyl, —(CH₂)₀₋₂-(aryl), —(CH₂)₀₋₂-(heteroaryl), or—(CH₂)₀₋₂-(heterocyclyl); R₁₄₀ is heterocyclyl optionally substitutedwith 1, 2, 3, or 4 groups independently selected from C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, amino (C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and ═O; R₁₅₀ is hydrogen, C₃-C₇cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ alkyl with one double bond and one triple bond, —R₁₁₀,—R₁₂₀, or C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀, and halogen;R₁₅₀′ is C₃-C₇ cycloalkyl, —(C₁-C₃ alkyl)-(C₃-C₇ cycloalkyl), C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl with one double bond and one triplebond, —R₁₁₀, —R₁₂₀, or C₁-C₆ alkyl optionally substituted with 1, 2, 3,or 4 groups independently selected from —OH, —NH₂, C₁-C₃ alkoxy, R₁₁₀,and halogen; R₁₈₀ is selected from morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyland pyrrolidinyl, each of which is optionally substituted with 1, 2, 3,or 4 groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁₋C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, and ═O; R₁₁₀ is aryl optionallysubstituted with 1 or 2 R₁₂₅ groups; R₁₂₅ at each occurrence isindependently halogen, amino, mono- or dialkylamino, —OH, —C≡N,—SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl),—CO—NH₂, —CO—NH—C₁-C₆ alkyl, or —CO—N(C₁-C₆ alkyl)₂, or C₁-C₆ alkyl,C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substitutedwith 1, 2, or 3 groups that are independently selected from C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- anddialkylamino, or C₁-C₆ alkoxy optionally substituted with one, two orthree of halogen; R₁₂₀ is heteroaryl, which is optionally substitutedwith 1 or 2 R₁₂₅ groups; and R₁₃₀ is heterocyclyl optionally substitutedwith 1 or 2 R₁₂₅ groups.
 2. A compound according to claim 1 with theproviso that neither R_(N) nor R_(N)′ is an alpha amino acid.
 3. Acompound according to claim 2 wherein R₂₀ at each occurrence is H; andR₁ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, —S—(C₁-C₃) alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or C₂-C₆ alkenyl orC₂-C₆ alkynyl, each of which is optionally substituted with 1, 2, or 3groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, amino, and mono- or dialkylamino.
 4. A compound according toclaim 3 wherein R₁′ is —CH₂-phenyl where the phenyl ring is optionallysubstituted with 1, 2, 3, or 4 groups independently selected fromhalogen, C₁-C₄ alkoxy, hydroxy, —NO₂, and C₁-C₄ alkyl optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalogen, OH, SH, NH₂, NH(C₁-C₆ alkyl), N—(C₁-C₆ alkyl)(C₁-C₆ alkyl),C≡N, CF₃.
 5. A compound according to claim 4 wherein R_(N) and R_(N)′are independently —C(═O)—(CRR′)₀₋₆R₁₀₀; and R₁₀₀ represents aryl,heteroaryl, heterocyclyl, where the ring portions of each are optionallysubstituted with 1, 2, or 3 groups independently selected from —OR,—NO₂, C₁-C₆ alkyl, halogen, —C≡N, —OCF₃, —CF₃, —(CH₂)₀₋₄—O—P═O—O)(OR)(OR′), —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—O—(CH₂)₀₋₄—CONR₁₀₂R₁₀₂′, —(CH₂)₀₋₄—CO—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO—(CH₂)₀₋₄(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R₁₁₀, —(CH₂)₀₋₄—R₁₂₀,—(CH₂)₀₋₄—R₁₃₀, —(CH₂)₀₋₄—CO—R₁₁₀, —(CH₂)₀₋₄—CO—R₁₂₀, —(CH₂)₀₋₄—CO—R₁₃₀,—(CH₂)₀₋₄—CO—R₁₄₀, —(CH₂)₀₋₄—CO—O—R₁₅₀, —(CH₂)₀₋₄—SO₂—NR₁₀₅R′₁₀₅,—(CH₂)₀₋₄—SO—(C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl),—(CH₂)₀₋₄—SO₂—(CH₂)₀₋₄—(C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(R₁₅₀)—CO—O—R₁₅₀,—(CH₂)₀₋₄—N(R₁₅₀)—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—N(R₁₅₀)—CS—N(R₁₅₀)₂,—(CH₂)₀₋₄—N(R₁₅₀)—CO—R₁₀₅, —(CH₂)₀₋₄—NR₁₀₅R′₁₀₅, —(CH₂)₀₋₄—R₁₄₀,—(CH₂)₀₋₄—O—CO—(C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R₁₁₀)₂,—(CH₂)₀₄—O—CO—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—CS—N(R₁₅₀)₂, —(CH₂)₀₋₄—O—(R₁₅₀),—(CH₂)₀₋₄—O—R₁₅₀′—COOH, —(CH₂)₀₋₄—S—(R₁₅₀), —(CH₂)₀₋₄—N(R₁₅₀)—SO₂—R₁₀₅,—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, and (C₂-C₁₋₀)alkynyl, orR₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups.6. A compound according to claim 5 wherein R_(N) and R_(N)′ areindependently —C(═O)-aryl or —C(═O)—heteroaryl optionally substitutedwith 1, 2, or 3 groups independently selected from —OR, —NO₂, C₁-C₆alkyl, halogen, —C≡N, —OCF₃, —CF₃, —(CH₂)₀₋₄—CO—NR₁₀₅R′₁₀₅ and—(CH₂)₀₋₄—N(R₁₅₀)—SO₂ —R₁₀₅, or R_(N) and R_(N)′ are independently—C(═O)—C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —CO₂R₁₀₂, —C₁-C₆ thioalkoxy,—CO₂-phenyl, —NR₁₀₅R′₁₀₅, —SO₂—(C₁-C₈ alkyl), —C(═O)R₁₈₀, R₁₈₀,—CONR₁₀₅R′₁₀₅, —SO₂NR₁₀₅R′₁₀₅, —NH—CO—(C₁-C₆ alkyl), —NH—CO—R₁₁₀,—NH—CO—R₁₂₀, —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl,—O—C(═O)—(C₁-C₆ alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino,—O—C(═O)-phenyl, —O—(C₁-C₆ alkyl)-CO₂H, —NH—SO₂—(C₁-C₆ alkyl), C₁-C₆alkoxy and C₁-C₆ haloalkoxy.
 7. A compound according to claim 6 selectedfrom the group consisting of:5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,5-(acetylamino)-1,2,5,6-tetradeoxy-7-s-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]1-1-phenyl-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,N-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-1-phenyl-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol,N′-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,N′-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-1-phenyl-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-1-phenyl-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-phenyl-D-glucitol,5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol,2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol,N³-[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,N³-[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol,2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-7-thio-D-gluco-heptitol,5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-D-gluco-heptitol,2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-D-gluco-heptitol,5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol,2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol,N′-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,N′-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-5-methyl-N,N-dipropylisophthalamide,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-S-methyl-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-7-O-methyl-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N-[(1S,2R,3R,4R)-4-(benzoylamino)-1(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-[(1S,2R,3R,4R)-4-(benzoylamino)-1(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[methyl(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,N-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-[({2-[(methylsulfonyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-D-glucitol,5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol,2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol,N³-[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,N³-[(1S,2R,3R,4R)-4(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]-N¹₁N¹-dipropylbenzene-1,3,5-tricarboxamide,5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-7-thio-D-gluco-heptitol,2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-7-thio-D-gluco-heptitol,5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-D-gluco-heptitol,2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-D-gluco-heptitol,5-(acetylamino)-2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol,2-({3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoyl}amino)-5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide,N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide,5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide,N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-benzyl-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide,5-(acetylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-S-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-7-O-methyl-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-phenyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide,N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)-4-propylheptyl]nicotinamide,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-5-propyl-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,N-[(1R)-1-({[(1S,2R,3R,4R)-4-(acetylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide,N-[(1R)-1-({[(1S,2R,3R,4R)-4-(benzoylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxyoctyl]amino}carbonyl)heptyl]nicotinamide,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-S-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-7-thio-D-gluco-heptitol,5-(acetylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,5-(benzoylamino)-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-7-O-methyl-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-gluco-heptitol,5-(acetylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol,and5-(benzoylamino)-6-cyano-1,2,5,6-tetradeoxy-1-(3,5-difluorophenyl)-2-({(2R)-2-[(pyridin-3-ylcarbonyl)amino]octanoyl}amino)-D-glucitol.8. A method for the treatment or prevention of Alzheimer's disease, mildcognitive impairment Down's syndrome, Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, otherdegenerative dementias, dementias of mixed vascular and degenerativeorigin, dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, diffuse Lewy body type of Alzheimer'sdisease compriseing administration of a therapeutically effective amountof a compound or salt according to claim 1, to a patient in needthereof.
 9. A method of treatment as in claim 8, wherein the patient isa human.
 10. A method of treatment according to claim 8, wherein thedisease is dementia.
 11. A method for making a compound of claim
 1. 12.An intermediate of the formula XI:

wherein Pg is an amine protecting group; R₁ is C₁-C₁₀ alkyl optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, —S—(C₁-C₃)alkyl, amino, mono-or dialkylamino, —N(R)C(O)R′—-, —OC(═O)-amino and —OC(═O)-mono- ordialkylamino, or C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which isoptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- ordialkylamino, or aryl, heteroaryl, heterocyclyl, aryl (C₁-C₆)alkyl-,heteroaryl (C₁-C₆)alkyl-, or heterocyclyl(C₁-C₆)alkyl-, where the ringportions of each are optionally substituted with 1, 2, 3, or 4 groupsindependently selected from halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅,—CO₂R, —N(R)COR′, —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino,—SO₂-monoalkylamino, —SO₂-dialkylamino, —C(═O)-amino,—C(═O)-monoalkylamino, —C(═O)-dialkylamino, —SO₂—(C₁-C₄) alkyl, C₁-C₆alkoxy optionally substituted with 1, 2, or 3 groups which areindependently selected from halogen, C₃-C₇ cycloalkyl optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- ordialkylamino, C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, and C₂-C₁Oalkenyl or C₂-C₁₀ alkynyl each of which is optionally substituted with1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino; andthe heterocyclyl group is optionally further substituted with oxo; R andR′ independently are hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkylaryl or C₁-C₁₀alkylheteroaryl; R₁′ is phenyl-(C₁-C₆)alkyl- where the phenyl ring isoptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′,—N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-monoalkylamino,—SO₂-dialkylamino, —C(═O)-amino, —C(═O)-monoalkylamino,—C(═O)-dialkylamino, —SO₂—(C₁-C₄) alkyl, C₁-C₆ alkoxy optionallysubstituted with 1, 2, or 3 groups which are independently selected fromhalogen, C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, —C₁-C₆ alkyl and mono- or dialkylamino, C₁-C₁₀ alkyl optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and—C₁-C₃ alkyl, and C₂-C₁₀alkenyl or C₂-C₁₀alkynyl each of which isoptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl andmono- or dialkylamino; and the heterocyclyl group is optionally furthersubstituted with oxo, with the proviso that R₁ and R₁′ are notsimultaneously unsubstituted phenyl-(CH₂)—.
 13. An intermediate of theformula B:

wherein Pg is an amine protecting group; and R₂₀ is H or C₁-C₆ alkyl; R₁is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃alkoxy, —S—(C₁-C₃)alkyl, amino, mono- or dialkylamino, —N(R)C(O)R′—,—OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or C₂-C₆ alkenyl orC₂-C₆ alkynyl, each of which is optionally substituted with 1, 2, or 3groups independently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃alkoxy, amino, and mono- or dialkylamino, or aryl, heteroaryl,heterocyclyl, aryl(C₁-C₆) alkyl-, heteroaryl(C₁-C₆) alkyl-, orheterocyclyl(C₁-C₆)alkyl-, where the ring portions of each areoptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —NO₂, —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′,—N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-monoalkylamino,—SO₂-dialkylamino, —C(═O)-amino, —C(═O)-monoalkylamino,—C(═O)-dialkylamino, —SO₂—(C₁-C₄) alkyl, C₁-C₆ alkoxy optionallysubstituted with 1, 2, or 3 groups which are independently selected fromhalogen, C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, —C₁-C₆ alkyl and mono- or dialkylamino, C₁-C₁₀ alkyl optionallysubstituted with 1, 2, or 3 groups independently selected from halogen,—OH, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and—C₁-C₃ alkyl, and C₂-C₁O alkenyl or C₂-C₁₀alkynyl each of which isoptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl andmono- or dialkylamino; and the heterocyclyl group is optionally furthersubstituted with oxo; R and R′ independently are hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ alkylaryl or C₁-C₁₀ alkylheteroaryl.
 14. The intermediate ofclaim 13 wherein R₂₀ is H.